Natural Cures For Prostate Cancer

The 21 Day Prostate Fix

21 Day Prostate Fix written by Radu Belasco is a healthier alternative to drugs and invasive medical procedures. Radu Belasco is an early prostate problem sufferer, with a family history of prostate pain, problems and cancer. Using a unique system of natural remedies, he fixed his prostate problems and wrote them in his smash hit eBook The 21 Day Prostate Fix. It is about miraculous herbs and fruits from all over the world. These unique foods have the power to cure your prostates inflammation in record time and shrink it to a healthier size. Also, you will learn how to concoct the miracle elixir that will not just cleanse your prostate, but also burn body fat. Aside from these, youll get topnotch information on nutrition, so you can keep your prostate healthy and your sex drive at its peak. Plus, youll learn other health conditions that might be contributing to your prostate issues, so you can also remedy them and get your body in its best shape ever.

The 21 Day Prostate Fix Overview

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Prostate Cancer Derived Secreted Cav1 Alters the Local Tumor Microenvironment

Mediated in part through the CSD-binding site interface. To demonstrate the biologic effect of these activities, we recently showed that adult male PBcav-1 transgenic mice had significantly greater prostatic wet weight and a higher incidence of prostatic epithelial hyperplasia than did their nontransgenic littermates 96 . Prostatic tissues from the PBcav-1 transgenic mice, which also had greater Cav-1 secretory activities than did those from their nontransgenic littermates, also showed greater immunostain-ing for proliferative cell nuclear antigen and P-Akt, less nuclear p27Ep1 in hyperplastic lesions, and increased resistance to castration-induced prostate regression. An important note is that orthotopic prostatic injection of androgen-sensitive Cav-1-secreting RM-9 mouse PCa cells resulted in tumors that were significantly larger in PBcav-1 mice than they were in the nontransgenic littermates 96 . These results demonstrate that prostate cell-derived secreted Cav-1 can result in...

The Definition of Benign Prostatic Hyperplasia

BPH is a progressive disease characterized by prostate stromal and epithelial cell hyperplasia, which usually begins in the periurethral zone of the prostate. This process can be asymptomatic or associated with lower urinary tract symptoms (LUTS), typified by urinary frequency and urgency, nocturia, decreased and or intermittent force of stream, and incomplete bladder emptying.9 BPH is extremely common one European survey of 80 774 subjects estimated that the prevalence of symptomatic BPH was 2.7 in men aged 45-49 years and 24 in men aged 80 years and over. Similar age-related trends have been observed in the USA, with an incidence of 34 100000 in 20- to 39-year-olds compared with a peak incidence of 1803 100 000 in 60- to 69-year-olds10 (see Table 1). Histopathologic evidence of BPH places the burden much higher, with a prevalence around 50 in men aged 60 years and 85 in men aged

The Pathophysiology of Benign Prostatic Hyperplasia

The prostate of aging males can be stimulated to undergo excessive growth. This is characterized by a number of cellular and molecular alterations leading to increased cell proliferation and reduced apoptosis in the prostate epithelium and stroma. The 'remodeling' that occurs as a result of these processes can permanently alter the appearance of the prostate, and may result in symptoms, long-term damage, and prostate cancer. It is not clear why these changes occur in some males, although it has been suggested that they are linked to a number of risk factors such as smoking, racial differences, obesity, liver cirrhosis, cardiovascular risks, and genetic predisposition. The pathogenesis of BPH is discussed in this section. A genetic involvement in the development and progression of BPH has been established. Molecular profiling using realtime quantitative reverse transcriptase-polymerase chain reaction on prostate tissue samples from BPH patients and normal controls has shown that at...

The Diagnosis of Benign Prostatic Hyperplasia

Several guidelines have been published to aid in the diagnosis of BPH the most prominent ones are those published by the American Urological Association (AUA)9 and by the European Association of Urology (EAU).29 Both of these guidelines recommend that the diagnosis of BPH is based on a medical history, symptomatic assessment using a validated instrument such as the International Prostate Symptom Score (IPSS), which uses eight items to categorize BPH 'urinary' symptoms as mild (IPSS 0-7), moderate (IPSS 8-19) and severe (IPSS 20-30), and a physical examination consisting of a digital rectal examination (DRE) to evaluate the prostate size. The AUA guidelines have produced a diagnostic algorithm, which is illustrated in Figure 10. The prostate-specific antigen (PSA) test is used to distinguish between BPH and prostate cancer. PSA, an endogenous serine protease secreted by the epithelium, is a key malignant tumor marker. At present, a number of methods are used to assess PSA (e.g., PSA...

Prostate Enlargement Benign Prostatic Hyperplasia

The prostate gland produces the fluid that surrounds and nourishes the sperm in semen. A common condition of older men is enlargement of the prostate gland (benign prostatic hyperplasia) three-quarters of men undergo some enlargement by their seventh decade. The prostate gland surrounds the urethra just below the bladder, and enlargement of the gland constricts flow of urine out of the bladder. This results in a frequent need to urinate, a slow, diminished stream of urine, and in- ability to fully empty the bladder. Although prostate enlargement can rarely be due to a cancer in the gland, in most cases, the process is benign and the cause unknown.

Micronutrients Prostate

Impaired zinc metabolism within the prostate gland may contribute to enlargement. Supplementation may reduce gland size and improve symptoms3 Supplementation may reduce risk of enlargement and prostate cancer1 prostate gland may contribute to enlargement. Supplementation can reduce activity of these substances and may reduce gland size and improve symptoms Fig. 5.31 Vitamin E supplementation and risk of prostate cancer. 30,000 50-69-year-old Finnish men were given 50 mg day alpha-tocopherol or placebo for 5-8 years. There were 151 new cases of prostate cancer in the placebo group, compared with only 99 new cases in the treatment group. (Source The ATBC Cancer Prevention Group. N Engl J Med. 1994 330 1029)

Introduction to the Prostate

Tgf Beta And Fgf

The prostate is a fibromuscular glandular organ involved in the male reproductive system. It is located between the bladder and pelvic floor, and surrounds the prostatic urethra. It is comprised of a large, nonglandular region and a smaller, glandular region that consists of epithelium and stroma, and can be further subdivided into three main zones the peripheral zone, which constitutes about 70 of the gland the central zone, comprising 25 of the gland and the transitional zone, which represents about 5-10 of the gland (see Figure 1). These zones have histological differences, mainly relating to secretory cell structure and the ratio of epithelium-to-stroma, which indicates that they have different functions.1 Figure 1 A sagittal section of the prostate, which shows anatomic subdivisions. (Reproduced with kind permission from Dixon, J. S. Gosling, J. A. Textbook of Benign Prostatic Hyperplasia, 2nd ed. Taylor & Francis London, 2005, pp 3-10 Taylor & Francis.) Figure 1 A sagittal...

Prostate cancer

Prostate cancer in teenagers is so rare that almost no epidemiological data have been published and the literature is confined to case reports 22 . Studies of early-onset prostate cancer (defined as diagnosed under the age of 55 years) generally only contain cases aged down to the mid 30s, but reveal associations with inherited polymorphisms of critical genes 23-26 . The impression gained from the few case reports of prostate cancer in the under-25 years age group is of tumors that are different biologically to those seen in the normal age range of elderly men. The tumors are usually undifferentiated, metastasize early, have lytic rather than sclerotic bone metastases, and respond poorly to hormonal therapies 22 . This is the opposite of what has been observed in bladder cancer. Patients may present with pelvic pain, dysuria, poor urinary stream, and possibly hematuria. Digital rectal examination may reveal clues to the diagnosis, but is relatively insensitive. Pelvic imaging by MRI,...

Diet Prostate

High-fat diets, particularly saturated fat from animal sources (meat, eggs, dairy products), promotes enlargement of the prostate and may also increase risk of prostate cancer.1,2 Diets high in fruits and vegetables, particularly those rich in lycopene (a carotenoid found in large amounts in tomatoes), reduce risk of prostate enlargement and cancer.1 Overactivity of certain prostaglandins within the prostate gland may contribute to enlargement. Substituting high-quality, cold-pressed plant oils for saturated fat in the diet, along with eating fresh fish two to three times per

Aberrant Cav1 Expression Complexity and Context

In contrast to studies of Cav-1 ' that revealed its potential tumor-suppressor activities, recently published study results showed that Cav-1 ' TRAMP (transgenic mouse prostate) mice demonstrate significantly fewer primary tumors and lesions than Cav-1*'* TRAMP mice do 101 . Additional studies showed that transgenic mice with targeted overexpression of Cav-1 in prostatic epithelial cells using the short probasin (PB) promoter (i.e., PBcav-1 mice) demonstrated prostatic hyperplasia 96 , In addition, secreted Cav-1 from prostatic epithelial cells in PBcav-1 mice created a local microenvironment that permitted tumor growth and increased serum Cav-1 that was associated with increased experimental PCa lung metastasis activities. These results are consistent with those of numerous studies that have documented Cav-1 overexpression in PCa tissues 75, 105, 108, 109 and other malignancies, including esophageal squamous carcinoma 34, 45 , oral carcinoma 35 , papillary carcinoma of the thyroid 38...

Caveolin1 Expression in Colon Cancer Human Colon Cancer Cell Lines

Indeed, similar variations in caveolin-1 expression linked to MDR and metastasis have also been observed in other cancer cell lines. Likewise, a significant amount of data is available in the literature associating elevated caveolin-1 levels in prostate, breast, and other cancers with angiogenesis, aggressive cancer recurrence, enhanced metastasis and generally reduced patient survival (reviewed in 111 ). More recently, caveolin-1 was found to represent an independent predictor of decreased survival and higher metastatic potential, not only in colon, but also in breast cancer 66 . Moreover, gene expression profiling identified caveolin-1, together with PKCa and Enolase 2 as the main targets up-regulated in HT29 cells resistant to methotrexate, while E-cadherin was repressed in resistant cells 126 . This result is remarkably similar to the aforementioned situation in HT29 cells, where HT29(US) with elevated metastatic potential, unlike the original HT29(ATCC) cells, essentially lack...

The Ambiguous Role of Caveolin1 in Cancer

The expression of caveolin-1 in colon tissue and cancer cell lines (see previous section). Furthermore, caveolin-1 is known to promote tumor formation and its presence is correlated with poor prognosis and survival in prostate cancer. Indeed, the expression of caveolin-1 reportedly increases in primary tumors from prostate 154 and certain leukemia-derived cell lines 52 , Also, in prostate cancer cells, caveolin-1 presence increases tumor growth and the incidence of metastasis 7, 67, 88, 136 . Increased caveolin-1 expression in tumor samples is not restricted to cases, like the prostate, where normal tissues have low relative caveolin-1 levels, since increased expression was also reported in tumor models where initial caveolin-1 loss is observed, such as colon 11 and breast cancer 38,42,123 . In most of these cases, the available data argue for a strong positive correlation between expression of caveolin-1, metastasis, and MDR ,42, 80, 81 , Moreover, studies in samples derived from...

Caveolin1 and the Proliferation of Cancer

Although Cav-1 has been shown in multiple settings to be critical for pancreatic tumorigenesis, the exact role of Cav-1 in pancreatic tumor cell promotion and survival is unclear. Recent data show its importance in a newly described tumori-genic mechanism involving the tumor microenvironment called the reverse Warburg effect 10 , Many previous studies suggest that Cav-1 is a tumor suppressor gene. For example, down-regulation of Cav-1 expression was observed in breast, lung, colon, and ovarian cancers 11-13 . Ectopic expression of Cav-1 in transformed normal cells and tumor cell lines inhibited cell growth in vitro and tumorigenesis in vivo. Further, Sunaga et al. reported that Cav-1 acted like a tumor suppressor gene in small cell lung cancer, whereas in nonsmall cell lung cancer it is required for cell survival and growth 14, 15 , In contrast, other studies have reported that Cav-1 expression was up-regulated in human cancers, including prostate cancer and esophageal squamous cell...

Caveolin1 as a Biomarker in Pancreatic Ductal Adenocarcinoma

We have demonstrated that Cav-1 expression correlated with poor differentiation status of PDA tumor and also correlated with fatty acid synthase (FASN) expression (Fig. 3.1) 35 . FASN is a lipogenic enzyme, which catalyzes the terminal steps of fatty acid biosynthesis 36 . Like Cav-1, FASN has been shown to be dysregulated in a number of cancers such as breast and prostate, where higher expression levels of FASN have been correlated with advanced tumor stage and poor prognosis 35, 37 . Expression of both Cav-1 and FASN has a positive correlation with malignant disease in PDA (Fig. 3.1). Conversely, a significant survival advantage was found in patients with low expression of Cav-1 37 . Specifically, Cav-1 and FASN expression are absent in precursor lesions of PDA, pancreatic intraepithelial neoplasia (PanlNs), and normal pancreatic ducts, but both may be elevated in PDA. The fact that Cav-1

Cav1 Is Down or Upregulated in Melanoma Cells

In addition, Cav-1 expression was found to positively associate with melanoma malignancy, being low in primary melanomas and highly expressed in cell lines derived from lymph node metastases (Table 5.1). In the same study, we detected a secreted exosome-associated fraction of Cav-1 in melanoma conditioned media (see Table 5.1), directly proportional to endogenous Cav-1 expression. Interestingly, this data was in line with another study on prostate cancer where serum levels of Cav-1 were proposed as diagnostic and prognostic markers 28 . In our experiments, Cav-1 expression in human melanoma-derived cell lines was unquestionably associated with its tumor-promoting function, while Cav-1 immunodetection on the corresponding melanoma tissues is still lacking. However, studies on GC demonstrated a stage-dependent Cav-1 expression with a biphasic differential function in original tissue and derived cell lines 4 , namely low in tissue and high in cell lines. In GC, Cav-1 appears as a...

Positive Role of Cav1 in Mouse Models of Tumor Growth and Tumor Induced Angiogenesis

A positive role of Cav-1 in tumor-induced angiogenesis in vivo has been reported using mouse B16 melanoma and RM-9 prostate cancer cells implanted in Cav-1 KO and wild type (WT) C57BL 6 mice or human prostate cancer LNCaP cells implanted into nude mice (see Table 6.1). Orthotopic prostate injection of mouse RM-9 cells Subcutaneous injection of human prostate cancer cells (LNCaP) in nude mice Comprehensive in vivo and in vitro evidence supporting a pro-angiogenic role for Cav-1 has recently been presented in another study 21 using an orthotopic RM-9 mouse prostate cancer model. Specifically, Cav-1 expressing and secreting RM-9 prostate cancer cells were injected directly into the dorsolateral prostate of male WT or Cav-1 KO mice. As in other studies, the mean tumor wet weight and density of CD31 positive microvessels were significantly reduced in Cav-1 KO relative to WT mice. Interestingly, a majority of the CD31 positive microvessels in the Cav-1 KO mouse tumor sections were also...

Correlative Evidence Supporting a Positive Role of Cav1 in Tumor Angiogenesis Based on Clinical Studies

Using double immunofluorescent labeling with antibodies to CD34 and Cav-1, it has been determined that the MVD values were also significantly higher in Cav-1-positive than in Cav-1-negative prostate cancer tumors 28 . Interestingly, Cav-1 positivity in microvessels within tumor specimens was significantly less frequent than in the blood vessels of benign prostatic tissues. In contrast, the percentage of Cav-1-positive tumor associated ECs in Cav-1-positive tumors was significantly higher than in Cav-1-negative tumors. This increased Cav-1 positivity in tumor-associated ECs was predominantly confined to regions with Cav-1-positive tumor cells, Prostate cancer corresponding to the higher percentage of Cav-1-positive microvessels within these regions, as opposed to Cav-1-negative tumors. These data suggest that prostate cancer cell-derived Cav-1 could be involved in mediating angiogenesis during prostate cancer progression in humans 28 .

Role of Cav1 in Apoptosis

The anchorage-independent growth of these cells in soft agar, an effect that appeared to be due in part to its ability to initiate apoptosis 73 . In addition, it has been reported that in mouse embryonic fibroblasts and in T24 bladder carcinoma epithelial cells, overexpression of Cav-1 induces apoptotic cell death through inhibition of PI3-kinase and or activation of caspase-3 74, 75 . Moreover, recent results from a DNA microarray analysis performed on Met-1 cells 50, 51 overexpressing Cav-1 have revealed the up-regulation of pro-apoptotic genes 52 . Taken together, these results provide evidences that Cav-1 has a pro-apoptotic role. However, it has been shown that up-regulation of Cav-1 in human prostate cancer cells causes resistance to apoptosis, and its antisense down-regulation induces apoptosis 47, 76, 77 , In conclusion, it seems that Cav-1 plays a controversial dual role in the apoptosis process. The apparent incongruity may depend on the cell type or cellular context.

CAFs Catalysts for TUmor Growth

Several studies have now demonstrated that CAFs represent a direct tumor-promoting force, as shown by co-culture and tissue recombination experiments, as they can drive the progression of benign cells to a frank tumorigenic phenotype. For example, the combination of normal prostatic epithelial cells with CAFs isolated from prostate tumors induced the formation of PIN (prostatic intraepithelial neoplasia)-like lesions. More interestingly, when the same experiment was repeated with the combination of immortalized prostatic epithelial cells and CAFs, the tumors that developed were 500-fold bigger than the graft that contained the same epithelial cells with NFs 15 . More precisely, the addition of CAFs altered the cell morphology, decreased the number of apoptotic cells, and increased the proliferation rate of prostatic epithelial cells 15 . Similar results were obtained when epithelial cells from the

Role of Caveolin1 as Tumor Suppressor in Colorectal Cancer Inhibition of bCatenin TcfLef Dependent Gene Expression

Initially, our entrance to the caveolin field came with the demonstration that caveolin-1 protein levels are reduced both in the mucosa and stroma of tumors from patients with colon cancer, as well as in colon adenocarcinoma cells and that caveolin-1 functions as a tumor suppressor in vivo upon re-expression in different colon adenocarcinoma cells 10, 11 . Despite the ever-increasing abundance of signaling molecules available in the literature for regulation by caveolin-1 at the time, relatively few were linked to specific transcriptional events. Thus, as one approach, we set out to compare, by microarray analysis, colon cancer cell lines expressing or not caveolin-1. Rather intriguingly, those studies identified in an initial screen the IAP protein survivin as one of the most strongly down-regulated targets at the transcriptional level 138 . This protein is of tremendous interest, since it is abundantly expressed in a variety of human tumors including lung, colon, breast, prostate,...

Cav1 in Skin Cancer

Skin cancer is the most common form of neoplasia in the United States. The two most common, but likely highly curable types, are basal cell cancer and squamous cell carcinomas. Conversely, melanoma is rare, but very aggressive. In the last decades, its incidence is steadily increasing in most countries, while not paralleled by the development of new therapeutic agents with a significant impact on survival. At present, early detected melanomas can be cured by surgical excision, while more advanced stages are difficult to control. Once melanomas metastasize, the median 5-year survival rate is less than 5 18 . At present, few data exist on Cav-1 expression and function in non-melanoma skin cancers. A microarray-based gene profiling showed increased Cav-1 expression in human basal cell carcinomas (BCC) as compared to normal skin, suggesting that it may play a dynamic role in controlling the slow progression of these tumors through both decreased cellular motility and tumor promotion 25 We...

Conclusions

Recent interesting reports have demonstrated that Cav-1 can also regulate tumor associated fibroblasts. In fact, stromal Cav-1 expression has been identified as a new prognostic biomarker for human breast cancer prognosis and therapy 88 . These findings may have important implications for the monitoring and stratification of breast cancer patients. Remarkably, a loss of stromal Cav-1 could also be used to predict ductal carcinoma in situ (DCIS) progression to invasive breast cancer nearly 15-20 years in advance 89 , In addition, more evidences suggest that a role for Cav-1 in the tumor stroma is not restricted to breast cancer patients as similar results have been obtained in prostate cancer patients 90 , Thus, a loss of stromal Cav-1 may be an important prognostic biomarker for other types of cancers besides breast and prostate.

Risk Factors and Cancer

Diet and obesity in adults account for 30 of all cancer deaths in the USA. Diet has been shown to play a significant role in the causation of cancer but little is known about how it plays its role as a carcinogen.15,18 Excessive fat in the diet raises the risk of colorectal and breast cancer and possibly prostate cancer. Adult obesity is associated with endometrial cancer, postmenopausal breast cancer, and cancers of the colon, rectum, and kidney.15,18 Obesity in concert with other risk factors such as low activity level, menopausal status, and predisposition to insulin resistance significantly increase the risk of cancer. While some methods of food preparation and preservation have been shown to increase the risk of various forms of cancers, certain classes of foods appear to contain protective substances against cancer including vegetables, whole grain products (fiber), and citrus fruits.12,15,18,20 Salt intake has been associated with risk of stomach cancer, but no other food...

Protein Zag A New Adipokine

A dramatic weight loss, entailing a reduction of the adipose organ by up to 85 , is a characteristic feature of tumour cachexia. Several factors are implicated in this process one of them is possibly ZAG (zinc-a2-glycoprotein), a 43-kDa protein originally isolated in human plasma 102 and later described in several organs breast, prostate, liver, lung and skin 103 . Overexpression of protein ZAG occurs in several malignant tumours and is thus used as a tumour marker.

Cancer Screening Diagnosis and Prevention

Thus far, biological markers (biomarkers) have been used to diagnose cancer, and to monitor disease progression and recurrence after therapy.59-62 Biomarkers have substantially improved the understanding of the molecular mechanism of action of carcinogenesis and risk, although they are more useful for monitoring the consequences of the disease and therapy rather than assessing the effects of risk factors on the onset of the disease. For example the serum-based markers calcitonin, prostate-specific antigen, and CA-125 are all elevated in medullary thyroid, prostate cancer, and a small subset of ovarian cancers, respectively.63-65 Urine-based biomarkers like bladder tumor antigen, survivin, and calreticulin have been recently used as diagnostic marker for bladder cancer.66 life-threatening cancer types. This is best exemplified for prostate and breast cancers which are diagnosed relatively early. Using biomarker analysis performed on the primary tumor recommendations can be made as to...

NCI directors consumer liaison group

This goal was achieved in August 1998 when the first Directors Consumer Liaison Group (DCLG) was selected, with a remit to provide input to the planning of programmes and future directions of research of the NCI. Setting up the initial DCLG involved careful planning by a group of NCI staff undertaken in collaboration with key cancer advocacy groups. Following response to an NCI call for nominations, fifteen members were selected by the NCI director. Nominees had to meet a series of eligibility requirements (summarised in Box 2.3) and were subject to an objective and pre-defined screening and evaluation process. The planning group recommended that the DCLG should reflect the breadth and depth of the cancer advocacy community and should therefore be multi-culturally diverse and include representation from a range of organizations and a broad mix of cancer sites. The initial membership, which was selected from 136 nominations, comprised mostly cancer survivors, but family...

Clinical studies cervical and other cancers

Effect of therapy on the immune system of cervical cancer patients undergoing external irradiation and intracavity brachytherapy with or without concurrent cisplatin and found that administration of concurrent cisplatinum with radiation therapy may have synergis-tically increased cytotoxic effects of radiation on tumor cells but did not alter the magnitude or characteristics of the radiation-induced immunosuppression. The role of concurrent radiation therapy and chemotherapy consisting of 5-fluorouracil and cisplatin was explored in the treatment of local-regionally advanced vulvar cancer and results appeared positive (143). The combination of cisplatin or carboplatin and radiation therapy has been discussed for locally advanced prostate cancer (144). Kaufman et al. (145) conducted a study of 34 patients to assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5-fluorouracil, and radiation therapy in conjunction with selective bladder...

Cellbased Cancer Vaccines

However, as the science of determining how an effective APC initiates an immune response advance, these strategies are being used to alter tumor cells and render them as loci of immune stimulation. The most general method for cell-based immunotherapy is to use a single representative cancer cell as a universal vaccine for all patients with that same type of cancer. Some investigators consider this approach as suboptimal as it is allogeneic, where the MHC type of the vaccine and the patient do not match, and the immune system may be distracted from generating a tumor-antigen-specific to an allospecific response. Others argue that an allogeneic vaccine will be effective for just this reason, and that the alloimmune response will serve to amplify the cancer-antigen-specific response. This issue will be addressed in Chapter 10, where Copier and Dalgleish discuss the use of whole tumor cells as vaccines in this unique approach to cancer therapy, as tumor-specific...

Recommended Daily Intakes

The usual therapeutic dose range is 15-45 mg day.10 Carotene supplements derived from natural sources are preferable. They contain, along with beta-carotene, a mixture of carotenoids, including lutein, alpha-carotene, and lycopene, and may have additional health benefits. For example, ly-copene is a potent antioxidant11 and may decrease the risk of prostate cancer and cataract.

Use in Prevention and Therapy

Vitamin A is one of nature's primary anticancer substances, particularly in the skin and mucous membranes. Ample intakes of vitamin A have been shown to protect against cancers of the lung, bladder, prostate, larynx, esophagus, stomach, and colon. Vitamin A can prevent precancerous lesions, such as oral leukoplakia (white patches on the lips and mouth often found in smokers) and cervical dysplasia, from developing and may produce regression and disappearance of these disorders.15 As a cancer treatment, large doses of retinoic acid may reduce growth and recurrence of certain forms of skin cancer.16 As an antioxidant, beta-carotene helps provide protection against damage from many xenobiotics (such as polychlorinated biphenyls PCBs ). It may also reduce the risk of skin cancer associated with exposure to sunlight6 and radiation.2

Treatment Options for Major Cancers and Future Directions

According to the most recent statistics, one in three people will be diagnosed with cancer during their lifetime. Increased life expectancy (cancer can be considered a disease of advanced years), environmental factors (e.g., exposure to carcinogens), and social habits (e.g., diet and or smoking) have dramatically increased the risk of cancer in Western populations. Breast, lung, colorectal, and prostate are the four major types of cancer in adults, and they account for over half of all cases diagnosed. The treatments of these major cancers depend upon a variety of factors, but the most common ones involved surgery combined with radiation and or chemotherapy. These treatments are briefly discussed in this section. Table 1 shows representative examples of anticancer agents and their mechanism of action.

The Antigen Specificity of Naturally Arising TR

The prevailing hypothesis regarding the TCR specificity of naturally arising regulatory T cells is that they recognize self-antigen, and that this interaction is important for TR development and function to suppress autoimmunity. This model was originally prompted by two studies in the 1990s that indirectly suggested that naturally arising TR recognize tissue-specific self-antigens. Initial studies by Taguchi and colleagues suggested that the functional maintenance of CD4+ Tcellscapableofprotectionagainst prostatitisoroophoritisrequired the presence of the corresponding organ, as adoptive transfer of T cells from male mice were more effective at preventing neonatal thymectomy-induced autoimmune prostatitis than oophoritis, and vice versa for T cells from female mice (Taguchi et al. 1994). Studies from Mason's group extended this observation by demonstrating that ablation of the thyroid gland resulted in the selective functional loss of T cells within the CD4+ population capable of...

Estrogen Receptors ERa and ER

Although estrogens are mainly produced locally by the ovaries, they exert systemic effects on selected target tissues. The action of the estrogens is mediated by two different estrogen receptors (ERs), ERa and ER 11 . ERa and ERjS are products of different genes and exhibit a tissue- and cell type-specific expression. The ERa is expressed primarily in the uterus, liver, kidney and heart, and sometimes it is co-expressed with the ER in mammary, thyroid and adrenal glands, in bone, and in the brain, where they can form functional heterodimers and where ER in many instances opposes the actions of ERa 11 . ERjS in contrast, is expressed specifically in the ovaries, in prostate, lung, in the gastrointestinal tract, bladder, and in the hematopoietic and central nervous system 11 .

FSee 708 Kinase Inhibitors for Cancer

Treatment options for prostate cancer include surgery and radiotherapy (e.g., external beam or radioactive seed implants, called brachytherapy see above).78 Hormonal treatment, chemotherapy, and radiation (or a combination of them) are used for metastatic diseases and as supplemental additional therapies for early stage tumors. Hormonal treatment, which controls the progression of the disease by shrinking the size of the primary tumor and reduces symptoms (e.g., pain), involves the use of antiandrogens to block production of testosterone, a hormone that prostate cancer cells use to grow. Examples of drugs used for this specific treatment include flutamide, leuprolide acetate, bicalutamide, and goserelin acetate. Bone metastasis is often associated with prostate cancer. The secondary tumor causes the breakdown of bone tissue releasing substantial amounts of calcium into the bloodstream. In order to treat the excess calcium in the blood (hypercalcemia), bisphosphonates (e.g., zoledronic...

Synthetic Carbohydratebased Vaccines

Our first vaccine constructs were monovalent in nature, composed of a single antigen conjugated to an immunogenic carrier molecule, such as KLH. In order to achieve appreciable levels of immunogenicity in mouse or human settings, these vaccine conjugates must be coadministered with an immunoadjuvant, in our case, QS21 7 . One of the original constructs to be synthesized in our laboratory was the Globo-H-KLH conjugate 8 . Globo-H, a hexasaccharide, was first isolated from the human breast cancer cell line (MCF-7) and later found to be overexpressed in a variety of other cancer cell lines, including colon, lung, ovarian, and prostate 9 . At the time, the synthesis of the Globo-H antigen was a significant undertaking, and provided an important platform for the evaluation of our glycal assembly protocol, outlined above (see Scheme 2.1). On the basis of these encouraging preclinical results, the Globo-H-KLH conjugate was advanced to phase I clinical trials against both prostate and breast...

Ligand Independent Activation of Steroid Hormone Receptors and Nongenomic Effects of Steroids

The GPR30 is expressed ubiquitously and expression in placenta, breast, ovaries, prostate, neural tissue, heart, endothelial, hepatic and lymphoid tissue has been shown 69 . GPR30 is co-expressed with the ERa in breast cancer tissue and breast cancer cell lines 70 . An exception is the human breast cancer cell line SK-BR-3, which is negative for the classic steroid hormone receptors ERa and ER but which does express the GPR30 endogenously. E2, but also the ERa antagonists 4-OH-tamoxifen and ICI 182,780 bind to cell membrane preparations of these cells with high affinity 67 . HEK-293 cells, which neither express the ERa, ER nor the GPR30, were transfected with a cDNA coding for GPR30. In membrane preparations of HEK-293 cells, GPR30-bound radio-labelled E2 was displaced by E2, 4-OH-tamoxifen, and ICI 182,780 67 . In contrast, knock-down of endogenous GPR30 in SK-BR-3 cells with specific small interfering RNAs (siRNAs) directed against the GPR30, decreased the binding of E2. Binding of...

Cadherins and epithelialmesenchymal transition EMT

Changes in expression of other cadherins accompanies downregulation of E-cadherin, in a situation reminiscent of the epithelial-mesenchymal transition that occurs during embryonic development. This transition is characterized by a loss of epithelial cell polarity and cell-cell contact, gain of mesenchymal markers such as N-cadherin, and an increased migratory phenotype.154 Increased levels of N-cadherin, normally expressed in neuronal cells and fibroblasts in adults, are observed in breast and prostate cancer and invasive melanoma.155 N-cadherin is thought to mediate a less stable and more dynamic form of cell-cell adhesion, and its overexpression enhances invasion and formation of metastasis. These changes occurred despite the presence of E-cadherin, suggesting that N-cadherin may play a dominant role. N-cadherin invasive activity occurs, at least partly, via association with the fibroblast growth factor receptor-1 (FGFR-1). Interaction results in stabilization of FGFR-1 leading to...

Cancer Immune Surveillance

Geneic BALB c mice (Dighe et al., 1994). These results showed that IFN-y had direct effects on tumor cell immunogenicity and played an important role in promoting tumor cell recognition and elimination. In the experiment with MCA-induced tumor formation, compared with wild-type mice, mice lacking sensitivity to either IFN-y (IFNGR-deficient mice) or all IFN family members (signal transducers and activators of transcription Stat 1-deficient mice Statl is the transcription factor that is important in mediating IFNGR signaling) developed tumors more rapidly and with greater frequency when challenged with different doses of the chemical carcinogen MCA. In addition, IFN-y-insensitive mice developed tumors more rapidly than wild-type mice when bred onto a background deficient in the p53 tumor-suppressor gene (Kaplan et al, 1998). IFN-y-insensitive p53- - mice also developed a broader spectrum of tumors compared with mice lacking p53 alone. The importance of this experiment lay in the...

Rationale for the Use of 5aReductase Inhibitors in Cancer Treatment

Steroid 5a-reductase is a membrane bound, NADPH-dependent enzyme that is responsible for the selective, irreversible conversion (reduction) of 4-ene-3-oxosteroids into the corresponding 5a-3-oxosteroids (Fig. 10). Two genes code for 5a-reductase activity, the 5a-reductase type 1 and type 2 (5aR-1 and 5aR-2), and they are only 50 homologous on the protein level 114 . 5aR-1 is mainly expressed in the sebaceous glands of the skin and in the liver, whereas 5aR-2 is expressed in androgen-sensitive tissues, i.e. prostate, epididymis and other reproductive tissues 115 . The 5a-reductases are important regulators of endocrine action in androgen-sensitive cells. The 5aR-2 isoenzyme has a high affinity for the most important substrate testosterone (Km 4-50 nM) while the affinity of the 5aR-1 for testosterone is considerably lower (Km 1-5 M). The physiological roles of testosterone and dihy-drotestosterone (DHT) are quite different. In males, testosterone determines the modification of external...

Chemistry of 5aReductase Inhibitors

The first 5aR-2 inhibitors were synthesised by modifying the structure of the natural substrate testosterone. Substitution of one carbon atom at the A- or B-ring by an hetero-atom, led to the discovery of potent inhibitors of 5aR-2 such as the 4-azasteroids, 6-azasteroids, 10-azasteroids, as well as steroidal carboxylic acid inhibitors 118 . Among all these compounds, only the 4-azasteroides finasteride and dutasteride are approved for the treatment of benigne prostate hyperplasia (BPH). Dutasteride (GI198745) emerged from a family of 6-azasteroids through modification of the steroidal struc Novel substituted benzoylbenzoic acids and phenylacetic acids inhibitors have been synthesised that exhibit IC50 values in the nanomolar range. The compounds turned out to be potent and selective human 5aR-2 inhibitors. The phenylacetic acid derivatives, equipotent to finasteride and more potent than the analogous benzoic acids (IC50 values 5 versus 23 nM) were the strongest inhibitors in this...

Plasminogen Activation and Cancer

Plasmin are inhibited by the action of specific inhibitors, plasminogen activator inhibitor (PAI-1) and a2-antiplasmin, respectively uPA is secreted as a proenzyme that is reciprocally activated by the action of plasmin. Activation of the cascade is locally confined by the high-affinity binding between uPA or pro-uPA and the cell surface receptor uPAR. Mice lacking uPA display defects in extravascular fibrin degradation while cooperation is observed in transgenic animals that coexpress uPA and uPAR.192 In a similar manner to MMPs, stromal cells appear to be the major sources of plasminogen activity in most tumors. The stromal cell type producing uPA depends on the origin of the tumor, myofibroblasts being responsible in breast and colon and macrophages in prostate cancer. Elevated levels of uPA and uPAR in the blood and tissue are associated with poor prognosis in many types of cancer, regardless of their respective sources.193,194 Manipulation of uPA levels by overexpression,...

Tumor Necrosis Family Apoptosis and Immune Surveillance

Upon entering the vasculature, mechanical forces contribute to the delivery of tumor cells to specific target organs. The relatively large size of solid tumor cells will tend to lead to their arrest in the first capillary bed they encounter. However, it apparent that tumors arising in particular organs have preferential secondary sites of metastasis, indicating that interaction between the cancer cells (seed) and the organ microenvironment (soil) can influence the fate of the cells.228 In addition to negative regulators, such as TNF ligand expression as described above, diverse factors that can promote the formation of tissue-specific metastasis have been postulated. Chemokines have been identified as key regulators of this process. Chemokines are soluble ligands that are involved in recognition and homing of multiple cell types, including hematopoietic cells, lymphocytes, and germ cells.229 Breast cancer cell lines, as well as carcinomas and metastasis, express high levels of the...

Tissue distribution

Most of the drug-conjugating UGT isoforms are expressed in the liver, but are also present at variable levels in extrahepatic tissues, particularly tissues that are responsible for the absorption or excretion of drugs, such as intestine, lung, and kidney. Human hepatic UGTenzymes include UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B11, and UGT2B17.102 The gastrointestinal tract contains UGT1A1, UGT1A8 (restricted to the colon) and UGT1A10, whereas UGT1A7 seems to be localized to in the esophagus, stomach, and lung. Human kidney UGTenzymes include UGT1A8, UGT1A9, UGT1A10, and UGT2B7. In fact, UGT2B7 levels in the kidney are similar to those found in the liver.106 UGT2B transcripts are found in steroid-sensitive tissues, including the prostate (UGT2B17) and mammary tissues (UGT2B11 and UGT2B28).99 Glucuronidation reactions are also readily detectable in the brain and placenta.102

Pharmacology of Progesterone Receptor Antagonists

Nevertheless, these clinical results suggest a potential benefit of adding PR antagonists to the panel of options for the treatment of endocrine-responsive breast cancer, especially in order to extend the therapeutic options in anti-estrogen refractory diseases. The extension of endocrine treatments to other tumour entities is also a promising approach for further developments. El Etreby et al. demonstrated that applying the PR antagonist mifepristone in combination with 4-hydroxytamoxifen increases the induction of apoptosis additively and down-regulates the apoptosis-inhibitory protein Bcl-2 in the human breast cancer cell line MCF7 194 . These results suggest a potential clinical benefit of adding a PR antagonist to anti-estrogen therapy of breast cancer patients. The effects of PR antagonists (onapristone) has also been investigated in other tumour types, both in classic endocrine-sensitive tumours such as prostate cancer and in non-classic endocrine-sensitive ones as...

The Concept of The Champion in Drug Discovery Benign Prostatic Hypertrophy and the Inhibition of 5aReductase

From time to time, a person in a non-managerial position will have a marked impact on the research organization by single handedly becoming the champion for a specific research project. To those who were privileged to interact with him, Dr Glen Arth served as a splendid example of a champion. Dr Arth, an outstanding experimentalist, had been one of the important players in Dr Sarett's total synthesis of cortisone, which was the only practical rather than 'formal' synthesis of this hormone. Later, Dr Arth championed the search for a treatment of a disease that burdens many elderly men, known as benign prostatic hypertrophy (BPH). In the 1950s, Merck started to take an interest in investigating the role of androgens in several disorders linked to male sex hormones such as prostate disease, acne, and 'male pattern baldness.' Critical to the eventual success of the program was the recognition in the late 1960s that the enzyme 5a-reductase converts the male hormone testosterone into the...

Rationale for the Use of Antiandrogens in Cancer Treatment

Prostate cancer is the most frequently diagnosed malignancy in males and ranks second only to lung cancer in terms of annual mortality. Great efforts have been made in the past to develop novel approaches to the treatment of prostate cancer. The two main options for the treatment of prostate cancer are limited to surgical removal by radical prostatectomy (if the tumour is organ-confined) or endocrine therapy (if the tumour has crossed the capsule). One major problem in the treatment of non-organ confined prostate cancer is that the currently available therapies are only palliative. For locally advanced or metastatic prostate cancer the only effective therapies are those targeting the androgen receptor (AR). As most prostate cancer cells initially grow androgen-dependently, androgen withdrawal results in the apoptosis and inhibition of tumour proliferation. Although the majority of patients (80 ) responds to endocrine therapy, almost all prostate cancer patients undergo a relapse after...

D CD44Hyaluronan Interactions in Tumor Invasion and Metastasis

There is long standing evidence that many solid tumors are enriched in hyaluronan (163). As far back as the beginning of the 20th century there was the description of a 'mucinous substance' associated with malignant breast carcinoma, analogous in nature to that found in umbilical cord (164). Higher levels of hyaluronan are associated with poor prognoses in many cancers including human ovarian, breast and prostate carcinomas (165-168). Coincident with this is the finding that CD44 is often upregulated in several of the same tumor tissues (36,169,170). Given the close association of extracellular matrix receptors participating in adhesion and migration, a predicted facilitatory role for CD44 during invasion and metastasis is well warranted. A necessary question is whether binding to hyaluronan is a necessary component of CD44's positive function in invasion and or metastasis. Bartolazzi et al. (171) demonstrated that stable transfectants of CD44H in human melanoma cell line MC acquired...

Chemistry of Antiandrogens

The biology and structure-activity relationships for the emerging class of AR antagonists have been discussed in many reviews 201 . Based on their structure, the known AR antagonists can be classified as steroidal or non-steroidal. A few steroidal compounds have been used as anti-androgens, including cyproterone acetate (CPA), which was originally developed for other therapeutic purposes. When CPA was evaluated for the originally intended use, the anti-androgenic activity manifested as an undesired side effect. CPA is a progestin that suppresses gonadotropin release and binds to the AR with relatively high affinity and inhibits the growth of prostate cancer cells 202 . It was proposed that non-steroidal ligands will have a high specificity for the AR, improve oral bioavailability, and achieve tissue selectivity. In addition, they might allow more flexible chemical modifications if deemed necessary. First, substituted toluidides such as bicalutamide, flutamide and nilutamide were...

Pharmacology of Antiandrogens

Anti-androgens competitively bind to the AR-LBD. In clinical use are CPA, flutamide, nilutamide and bicalutamide. The first steroidal anti-androgen CPA has been reviewed extensively 202 . CPA suppresses gonadotropin release and leads to a decrease of testosterone levels. Flutamide and bicalu-tamide are non-steroidal compounds widely used in prostate cancer treatment. Bicalutamide 208 has replaced flutamide and nilutamide as the anti-androgen of choice for prostate cancer treatment since it has less side effects and a longer half-life. It is therefore administered at a relatively lower dose of 50 mg day. Response rates of bicalutamide in phase II clinical trials were comparable to those of CPA and flutamide 209 . In ongoing phase III studies, bicalutamide was compared with androgen ablation or maximal androgen blockade. Interim analyses confirmed the improved tolerability of bicalutamide however, the compound failed to improve survival 210,211 . Combined androgen blockade, first...

Hormone Interference Estrogens and Progestins

Prior to the introduction of tamoxifen, high-dose estrogens such as diethyl-stilbestrol (DES) or ethinyl estradiol were generally considered the endocrine treatment of choice for post-menopausal women with breast cancer and for men with prostate cancer 221 . Subsequently, the use of estrogens declined, but data from recent clinical trials underline that these drugs have a similar efficacy as tamoxifen and are able to produce responses, even in patients who have received extensive prior endocrine therapy. However, the use of these agents is limited by their toxicity profile. The mode of action of high dose estrogens is still under discussion. Besides a negative feedback regulation of the hormonal cycle, cytotoxic effects and induction of apoptosis have been proposed 222 . A modification of the treatment schedule and new formulations like sulfamates, phosphates or esters, which avoid the primary liver passage of the estrogen, may lead to a renaissance of this very effective treatment...

Rationale for the Use of Inhibitors of Releasing Hormones in Cancer Treatment

Prostate cancer and breast cancer are both stimulated by steroid hormones. The synthesis of estrogens and androgens is initiated by gonadotropins. In pre-menopausal women, gonadotropin-releasing hormone (GnRH) is released from the hypothalamus in a pulsatile fashion and is carried by the portal veins directly to the anterior pituitary gland where it binds to GnRH receptors, stimulating the release of luteinising hormone (LH) and follicle stimulating hormone (FSH) (Fig. 17). The ligand-bound receptors cluster and are taken up into the pituitary cells. These inactivated G protein-coupled GnRH receptors are replaced by newly synthesised receptors on the cell surface, ready for the next pulse of GnRH. LH stimulates the ovaries to produce

Telomeres And Direct Proof Of Their

Many reports have appeared suggesting a telomere-independent mechanism of cellular senescence is present in epidermal keratinocytes (39,40) and in mammary (39), adenoid (41), thyroid (42), and prostate (43) epithelial cells. The investigators who reported these findings found that inactivation of the p16 pRB pathway (by methylation of the p16 gene or by expression of viral oncogenes such as the human papilloma virus protein E7) was required before telomerase could immortalize these epithelial cells. Many of these epithelial cells were grown in a chemically defined medium in which the proliferative life span of 10-20 doublings is much less than the approximately 50 doublings that are seen when keratinocytes are grown on feeder layers (44). We have shown that keratinocytes can be immortalized by telomerase alone without inactivating p16 when grown in the more hospitable environment provided by feeder layers (which produce additional growth factors, extracellular matrix and or epithelial...

Application Of Proteomics To Diagnostic Marker Development

Taken one step further, proteomic techniques may directly be used as future diagnostic tools. The development of methods such as laser capture microdissection (LCM), ProteinChip technology, and surface-enhanced laser desorption ionization (SELDI) mass spectrometry may allow high-throughput analysis of very small samples to compare the entire protein profile between control and patient samples. Wright et al. applied ProteinChip proteomics to search for prostate cancer biomarkers (82). The authors analyzed tissue and body fluid, and found expression level changes to a number of proteins. Interestingly, a combination of several proteins, and no single protein alone, was required to distinguish between cancer and non-cancer patient groups. Once again, the identification of one specific marker protein may well be insufficient, and instead the protein fingerprint concept may be required for accurate diagnoses. Furthermore, in combination, ProteinChip and SELDI technologies may also allow...

The Discovery of ICI46474

Although the discovery of ICI46,474 (tamoxifen) (Figure 4), the antiestrogenic, pure trans isomer of a substituted triphenylethylene, was made by Harper, Richardson, and Walpole45-47 as part of the Fertility Control Program at ICI Pharmaceuticals (now AstraZeneca), Cheshire, UK, the study of cancer therapies was Walpole's long-term interest.48 In the late 1940s Walpole was a member of staff at ICI's Dyestuffs Division Biological Laboratory in Wilmslow, Cheshire. This establishment was the fledgling predecessor of the Pharmaceuticals Division Research Laboratories built in 1956-57 at Alderley Park near Macclesfield, Cheshire. Walpole was asked to establish animal models for the bioassay of potential alkylating agents49-54 to evaluate compounds as bladder carcinogens55 and to assess the potential health hazards for workers in the dyestuffs industry.56 Walpole made the important discovery that tris-ethyleneimino-S-triazine (M9500) was an active anticancer agent in the Walker rat...

Risk Of Second Malignancies

In an epidemiological study of HCL in Los Angeles County in 1990, it was noted that patients with a history of HCL were more than twice as likely as other cancer patients to have multiple cancer diagnoses.5 Since that time, multiple studies have confirmed that HCL patients have an increased risk for secondary malignancies. The rationale for this observation is probably dual. The primary treatment of HCL involves the use of nucleoside analogs, which lead to prolonged immunosuppression, with lower than normal numbers of CD4+ cells for more than 3.5 years.1819 This prolonged immunosuppression leads to an increase in second malignancies.19 Cheson et al. looked at patients with either chronic lymphocytic leukemia (CLL) or HCL who had undergone treatment with Nucleoside Analogs and found a total of 150 secondary cancers in 146 patients. Most of these cases were solid tumors, with a higher than expected frequency of prostate cancer.20 In a study from British Columbia, Au et al. reported that...

Conclusion and Outlook

Blocking steroid receptor function, by antagonists or inhibitors of steroid synthesis, inhibits or even prevents breast or prostate tumour growth. While the first anti-hormones were found accidentally, a deeper understanding of the steroid receptors as transcription factors and of the pathways of steroid hormone synthesis enabled more rational, structure-activity relationship-based drug discovery. Steroid hormone antagonists still have unspecific side effects and improvement of receptor and even tissue selectivity is the challenge for future research in this field. The development of compounds that block the interaction of agonist-liganded nuclear hormone receptors with co-factors might provide unique pharmacological agents for interrupting the signal transduction cascade 239 .

Targeted a Particle Nano Generators

More recently, 225Ac has been conjugated to a variety of MAbs using the bifunctional chelate SCN-DOTA. 225Ac has a 10-d half-life and decays by a emission through three atoms, each of which also emits an a particle. In vitro, 225Ac coupled to internalizing MAbs specifically killed leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer cells at doses 1000 times less than 213Bi-containing radioimmunoconjugates. In xenograft models of disseminated human lymphoma and solid prostate carcinoma, single doses at nanocurie levels of tumor-specific constructs prolonged survival and cured a substantial fraction of animals without toxicity (49). Therefore, in this strategy, 225Ac-SCN-DOTA serves as an atomic nano-generator that delivers a cascade of four a particles to the inside of a cancer cell by an internalizing antibody. A phase I trial of 225Ac-HuM195 in advanced myeloid leukemias is planned.

Central Dogma Of Tumor Progression

Actually be the same genes involved in a selective growth advantage for these cells. These cells maybe lurking even in early-stage cancers. That is, some cancers are predestined almost from the beginning to evolve into invasive, metastatic tumors and some are not. This possibility has huge implications for cancer screening, diagnosis, and choice of therapy. Numerous women receive a diagnosis of ductal carcinoma in situ of the breast based on mammography screening, and many men receive a diagnosis of prostate cancer based on a prostate-specific antigen (PSA) test and subsequent biopsy. And yet many of these patients have indolent tumors that would not affect their overall life expectancy, and they still often undergo significant surgical and drug treatments. The problem is that we are only beginning to be able to tell (e.g., by gene expression arrays) which of these so-called early-stage cancers will be lethal and which ones won't.

Figure 2 Contemporary preclinical drug development process

On the organ or stromal environment of the growing tumor and this can be helpful when working with targeted agents. In addition, the PK PD relationships in different tumor-containing organs can be evaluated. However, relative to flank models, orthotopic and metastatic model systems often have increased complications associated with staging of trials and, without sensitive imaging technologies and or genetic alteration of tumors cells, the inability to monitor tumor sizes remains a drawback. Furthermore, without tumor staging, these models can require large cohorts of tumor-bearing animals for convincing statistical analysis. These models also often require a high degree of technical skill and can be quite time-consuming, thus potentially restricting the size of trials that can be conducted. However, the evaluation of biomarkers in selected orthotopic or metastatic models, such as prostate-specific antigen (PSA) in the LuCap 23.1 (human prostrate carcinoma) or CA15-3 in the MDA-MB-231...

Changes in the bone formation markers with disease and therapy

The alterations in circulating levels of the bone formation markers differ depending on the type of bone disease present and the type and duration of therapy the patient receives. For example, the acute administration of large doses of glucocorticoids elicits a decrease in the serum concentrations of PICP and osteocalcin within 3 hours, whereas no changes are observed in the serum concentration of BAP 11 . The effect of oestrogen therapy can be monitored with just about any bone formation marker assay, although the response of intact PINP is about twice that of PICP 8 . In this clinical situation, the intact PINP assay seems to be superior to any other marker of either bone formation or resorption, since the extent of the biological variation is only about one-half of that of the treatment response 15 . In contrast, bone-specific and even total serum alkaline phosphatase are superior markers in Paget's disease of bone, in which disease PICP and osteocalcin are of limited value....

Analysis of Cytotoxic Agents in Xenograft Models

The data include several examples of cytotoxic agents that show significant xenograft activity that is reflective of clinical activity irinotecan is highly active in several models of colon cancer, temozolomide is efficacious in a model of glioma and one of two models of melanoma, paclitaxel is active in models of bladder, breast, lung, and prostate cancer, rituximab is highly active in two models of B-cell lymphoma, and gemcitabine is active in a model of pancreatic cancer. Note, however, that this activity can be quite dependent on the dose and schedule employed (note irinotecan in colon cancer models). Correlating dose and schedule with PK (e.g., efficacy driven by Cmax, area under the curve (AUC), time over threshold, etc.) is a vital aspect of preclinical evaluation in order to help define the optimum clinical schedule (once- versus twice-daily administration, continuous versus intermittent therapy, etc.). Table 1 also highlights some of the differences in activity that can be...

Inflammatory pathway in atherosclerosis biological basis of biomarkers in prediction and prognostication in

As data concerning the utility ofbiomarkers of inflammation in prospective cardiovascular risk prediction emerged, they appeared to fit into a pattern. One theoretical construct may help to systematize the biological basis ofbiomarkers ofinflammation in the cardiovascular arena (Fig. 4) (30). According to this hypothesis, a first wave ofprimary proinflammatory cytokines could arise from either vascular or extravascular sources (Fig. 4, top). Examples of primary proinflammatory cytokines include the soluble mediators IL-ip and tumor necrosis factor (TNF)-a. Intravascular sources could include the atheroma itself, a hotbed of inflammatory signaling, as already discussed. Extravascular sources could include foci of chronic infection, such as prostatitis, bronchitis, periodontal disease, or stasis or ischemic ulcers. Unfortunately, another potential source of extravascular inflammatory stimuli, visceral adipose tissue, will become more prominent owing to the currently increasing...

Nonspecific Immune Modulation Plus Active Immunotherapy

Striking synergy between anti-CTLA-4 antibody and autologous GM-CSF-secreting B16 melanoma and SM1 breast tumor vaccines against established disease in mice has been observed, and the antibody has also been tested in combination with an off-the-shelf GM-CSF-secreting prostate cancer vaccine, with promising results in preclinical studies (84-86). In a preliminary study in human cancer patients previously treated with either autologous or off-the-shelf cancer vaccines who went on to receive infusion with anti-CTLA-4 antibody, only those patients who received the autologous vaccine demonstrated signals of clinical activity (87). Many additional clinical trials are underway testing anti-CTLA-4 antibody either as monotherapy or in combination with off-the-shelf peptide vaccines, GM-CSF, and off-the-shelf whole cell vaccines (88,89 and http www.clinicaltrials.gov ). Unfortunately, there are no clinical trials currently underway testing anti-CTLA-4 antibody with personalized cancer vaccines...

Current and Future Applications Preclinical Research Applications

Dynabeads CD3 CD28 and Dynabeads ClinExVivo CD3 CD28 have been and continue to be used extensively in preclinical studies evaluating the use of novel adoptive T cell transfer approaches for treating cancer, infectious disease, autoimmunity, and disorders associated with chemotherapy and allogeneic transplantation. T cells have been effectively expanded from cancer patients, chronic lymphocytic leukemia CLL 38 , multiple myeloma MM 57 , non-Hodgkin's lymphoma NHL 50,58 , renal cell carcinoma RCC 59 , prostate cancer PC 60 , breast cancer BC 45 , HIV-infected patients 61,62 , and patients with autoimmune disease 63-65 .

Central Neural Mediation of Cytokine Induced Anorexia

The major hypothalamic detection site for blood-derived signals. Yet, severing the ARC from PVN or its connections with the PVN only slightly attenuated peripheral IL-1p-induced anorexia 35 , indicating that the ARC is involved but not necessary for peripheral IL-1p-induced anorexia. Several lines of evidence 20 implicate activation of hindbrain to forebrain aminergic neurons in the feeding suppression and hypermetabolic effects of circulating IL-1 p. IL-1p-induced anorexia may in part be mediated through prostaglandin E2-dependent activation of serotoninergic neurons originating in the raphe nuclei and projecting to the hypothalamus 36 . In line with this idea, systemic administration of a serotonin (5-HT2c) receptor antagonist and microinjection of the 5-HT1A autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) directly into the raphe nucleus both markedly attenuated the feeding-suppressive effect of peripherally injected IL-1-p 3 . Interestingly, anorexia...

Disclaimer Not for patient use To be used as a research guide only

CEA, carcinoembryonic antigen CA-125, cancer antigen-125 PSA, prostate-specific antigen SNPs, single nucleotide polymorphisms EGFR, epidermal growth factor receptor kinase-P, kinase phosphorylation PARP inhibition, poly(ADP-ribose) polymerase inhibition. Figure 3 Types of biomarkers. CEA, carcinoembryonic antigen CA-125, cancer antigen-125 PSA, prostate-specific antigen SNPs, single nucleotide polymorphisms EGFR, epidermal growth factor receptor kinase-P, kinase phosphorylation PARP inhibition, poly(ADP-ribose) polymerase inhibition.

Chemoattractant For Monocytes

The identification and cloning of MCP-1 provided an opportunity to screen tumors for their expression of a bona fide monocyte-specific chemoattractant. Table 1 lists several types of cell lines, tumor explants, and primary tumor tissues that express MCP-1. Although the list appears to be extensive, MCP-1 expression is not a universal property of tumor cells since there are many tumor types that do not express MCP-1, e.g., prostate carcinoma and many lung cancers (44).

Strategies to Modulate Treg Number and Function

Of the available cytotoxic agents leading to Treg depletion, cyclophosphamide (Cy) is the best described, although the depletion of Tregs is not always reproducible (Audia et al. 2007). Cy is known to deplete CD4+CD25+ Tregs in vivo in mouse models (Ghiringhelli et al. 2004) and decreases the suppressive capacity of Tregs in vitro by reversibly decreasing the expression of GITR and FoxP3 (Lutsiak et al. 2005). When low-dose Cy was used in combination with GM-CSF secreting cellular vaccine (Gvax) in mice bearing endogenous prostate tumors (Pro-HA x TRAMP), a significant decrease in tumor burden was observed that correlated with decreased numbers of Tregs in the prostate and more activated DCs in the draining LN (Wada et al. 2009). Similarly, clinical trials have demonstrated that low-dose Cy used in a metronomic regimen showed increased anti-angiogenic and immunostimulatory properties and a decrease in Treg numbers in peripheral blood (Ghiringhelli et al. 2007 Lord et al. 2007),...

Tumorassociated Antigens

Tumor-associated antigens are proteins expressed specifically on tumor cells, or more frequently, self-antigens that are overexpressed on tumor cells 22,23 . The goal of cancer immunotherapy is to elicit an immune response against these TAAs, triggering T cells to directly attack and kill tumor cells. As such, many viral vectors have been created that express TAAs such as carcinoembryonic antigen (CEA) or prostate-specific antigen (PSA). Several clinical trials have been conducted using a recombinant vaccinia virus expressing a TAA, and have shown that immune responses to the TAA can be elicited in cancer patients. A phase I clinical trial was conducted in which a recombinant vaccinia virus expressing CEA (rV-CEA) was given to patients with advanced carcinoma. While no significant antitumor effect was observed, the safety of giving advanced cancer patients a recombinant vaccinia vector was established, and CTL lines generated from patients were able to lyse tumor cells expressing CEA...

Epidemiology And Routes Of Transmission

The virus has not yet been found in fecal matter, but viral DNA can be detected in the semen by the polymerase chain reaction (PCR) technique. It has been reported that HHV-8 can be detected in the PBMCs in between 12 and 25 of homosexual men with KS but has not been consistently detected in semen samples of HIV-infected men without KS or from HIV-negative men (26-28). HHV-8 infections of the urogenital and prostate tissue of healthy men also do not appear to occur frequently. Therefore, the role of HHV-8 transmission via semen is still not clear. Apart from the implication of a linkage between HHV-8 infection and sexual activity suggested by the strong correlation between HHV-8 infection and homosexuality in North America and northern Europe, convincing evidence of heterosexual transmission of HHV-8 has not as yet been found. There are studies suggesting that commercial sex workers are more likely to be

Physiological Role of Desacyl Ghrelin

Pressing des-acyl ghrelin showed small pheno-type, which is not attributed to poor nutritional condition. It has been found that overexpressed des-acyl ghrelin acts in the pituitary and in the hypothalamus in transgenic mice, suggesting a role of des-acyl ghrelin in the regulation of GH secretion 18 . Moreover, recent studies indicated that ghrelin and des-acyl ghrelin exhibit similar GHS-R-independent biological activities, including a cytoprotective effect on cultured cardiomy-ocytes and endothelial cells 19 , the inhibition of cell proliferation in human breast and prostate cancer lines 20, 21 , the reduction of glycerol released from rat epididymal adipocytes 22 , and the promotion of adipogenesis directly in vivo in bone marrow fat 23 . Overall, these findings suggest that the action of des-acyl ghrelin is mediated by an as-yet unknown receptor that is different from GHS-R1a.

Identifying key symptoms

Sometimes more than one symptom may be important. For instance, patients may present with a complex mixture of symptoms which the treatment should palliate. In this situation a combination score or an algorithm maybe considered. In a trial assessing the value of mitoxantrone and prednisone in twenty-seven patients with hormonally resistant prostate cancer, Moore etal. 40 pre-defined a palliative response as a decrease in analgesic score by > 50 per cent or a decrease in 'present pain intensity' by > 2 points without an increase in analgesic score. In this phase II study nine patients were considered 'palliated' using this trial-specific definition, compared with only one who showed a traditional partial response. In an MRC Lung Cancer Working Party trial 41 comparing oral chemotherapy versus standard intravenous chemotherapy in patients with small cell lung cancer, QL was considered to be a primary outcome. In order to be considered 'equivalent' the oral treatment was required 'to...

Cytokine Model in Brain Responses

The simultaneous up-regulation of cytokines in peripheral organs and brain regions in response to a peripheral pathophysiological process has been reported during peripheral tumour development, peripheral cytokine administration, peripheral inflammation, and peripheral bacterial products challenge. For instance, rats bearing prostate gland adenocarcinoma cells exhibit cytokine mRNA (as an index of local production) up-regulation in the peripheral tumour, in peripheral organs such as the spleen and in discrete brain regions 31 . This cytokine up-regulation in the periphery and brain has also been observed in a non-hormone-dependent (non-adenocarcinoma) methylcholanthrene tumour model in rats 32 . In this model, intrahy-pothalamic administration of IL-1 receptor antagonist improved feeding 33 . There are also

Antitumor Sulfonamides

The development of CAIs possessing potent tumor cell growth inhibitory properties was reported by this group (Supuran and Scozzafava 2000b, 2000c Scozzafava and Supuran 2000a Supuran et al. 2001). Such compounds were discovered in a large screening program in collaboration with the National Institutes of Health (NIH) of sulfonamide CAIs. Several hundred aromatic heterocyclic sulfonamides were assessed in vitro as potential inhibitors of growth of a multitude of tumor cell lines, such as leukemia, nonsmall cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancers. The active compounds (most of them nanomolar inhibitors of CA II and CA IV), of types 4.212 to 4.223, belong to both the aromatic and the heterocyclic sulfonamide classes and showed GI50 values (molarity of inhibitor producing a 50 inhibition of tumor cell growth after a 48-h exposure to the drug) in the micromolar range (Supuran and Scozzafava 2000b, 2000c). Better antitumor compounds were then...

Angiogenesis and Cancer

VEGF overexpression is associated with tumorigenesis and a poor prognosis in a multitude of cancers, including gastric carcinoma (Maeda et al. 1996), colorectal carcinoma (Lee et al. 2000 Takahashi et al. 1995), lung cancer (Fontanini et al. 1997), melanoma (Gorski et al. 2003), prostate cancer (George et al. 2001), breast (Berns et al. 2003), and ovarian carcinoma (Paley et al. 1997). VEGF is upregulated in cancer cells in vivo by hypoxia and starvation (Zhang et al. 2002), and also by oncogene activation, which drives constitutive VEGF overexpression (Zhang et al. 2003b). VEGF directly promotes tumor angiogenesis through multiple mechanisms such as endothelial cell proliferation and survival, endothelial cell migration, vessel destabilization via Tie-2 (Zhang et al. 2003c), and enhancing chemotaxis of bone marrow-derived vascular precursor cells (e.g., endothelial cells, pericytes, vascular leukocytes) (Conejo-Garcia et al. 2004 Ellis and Hicklin 2008). In addition, VEGF promotes...

Role Of Various Factors In The Development Of Cancers

When populations move from one country to another, the rates for many cancers tend toward that of the local population rather than that of their country of origin. A classic example is the incidence rates among Japanese individuals living in Osaka, Japan, in contrast to those who have moved to Hawaii (Fig. 3-9).49 Within a generation, the incidence for prostate, colon, and breast cancer begin to approach those of the United States population, whereas the incidence of stomach cancer, more prevalent in Japan, decreases. Another interesting point from the data in Figure 3-9 is that from 1970-71 to 1988-92, some of the ''more Western cancers'' became more prevalent in Japan, presumably because of a more Westernized diet and lifestyle.

Provenge SipuleucelT Dendreon Seattle WA US

Provenge consists of autologous (patient-derived) DC that have been cultured with a delivery cassette that contains a version of the prostate cancer-associated antigen prostatic acid phosphatase (PAP) (found in about 95 of prostate cancers) and the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). It is designed to activate specialized immune cells called T cells to recognize and destroy cells bearing the PAP antigen. In contrast to personalized vaccines using patient's own tumor to derive a large repertoire of antigens, Provenge uses a generic antigen common in prostate carcinoma. A phase 3 trial of Provenge involving 127 patients with asymptomatic, androgen-independent, metastatic prostate cancer (study D9901) missed the primary end point of time to progression. However, the final three-year follow-up data showed a median survival benefit of 21 , or 4.5 months, and a threefold improvement in survival at 36 months compared with placebo, regardless of Gleason score...

The Endothelin System

The endothelin axis has been speculated to play significant roles in tumorigen-esis. Endothelin or the endothelin receptors or both are upregulated in a number of cancers including ovarian, breast, renal, colon, and prostate cancer (Bagnato and Rosano 2008 Nelson et al. 2003). Importantly, the use of specific endothelin receptor antagonists has been demonstrated to slow tumor growth in patients, or prevent tumor growth in mouse models (Bagnato and Rosano 2008 Nelson et al. 2003). In addition to its role in angiogenesis described in more detail below, the endothelin axis is believed to activate autocrine paracrine loops that promote proliferation, protection from apoptosis, immune evasion, vasculogenesis, and invasion and metastatic dissemination of tumors (Bagnato and Rosano 2008 Nelson et al. 2003).

Tyrosine Kinase Inhibitors

With respect to PDGF-R as a target, patients with CMML with a (5 12) translocation resulting in expression of the constitutively active Tel-PDGF-R fusion protein tyrosine kinase are an ideal target. STI571 has shown in vitro inhibition of leukemic cell lines expressing Tel-PDGF-R, and this finding has been corroborated in patient studies where remarkable clinical benefits with STI571 have been observed (57,82). Glioblastomas, the most common brain tumor and a highly chemotherapy- and radiation-resistant tumor, are associated with an autocrine growth loop involving PDGF and its receptor. STI571 inhibits the growth of glioblastoma cells injected into the brains of nude mice, suggesting that this agent could have potential as therapy for this currently incurable disease (83). Numerous other malignancies have also been reported to have autocrine activation of PDGF-R, including non-small cell lung, breast, and prostate cancers and several sarcomas however, the data supporting a role for...

Clinical Indications of Hyaluronan in Cancer

The increased accumulation of HA may thus provide an independent prognostic marker of ovarian cancer. The molecular basis for increased HA was not precisely defined but the action of growth factors and direct cellular contact with local mesenchymal cells was thought likely to have a role. Interestingly this is supported by previous studies which have shown that murine ovarian cancer cells stimulate HA production on murine mesenteric surfaces and tumour cell clumps (28). The evaluation of epithelial ovarian tumours was extended further by Hiltunen et al. (21), where HA accumulation alone, without hyaluronidase activation (the enzyme family which breaks down HA), was shown to correlate with the aggressiveness of ovarian cancer. In a prostate cancer study Posey et al. (25) evaluated the potential of HA and the Prostate cancer hyaluronidase family member, hyal-1, as prognostic markers in 70 clinical prostate cancer samples using a biotinylated HA-binding protein and anti-hyal-1 antibody....

Management of nongastric localizations

The stomach is the most common and best studied site of involvement, but MALT lymphomas have also been described in various non-GI sites, such as salivary gland, thyroid, skin, conjunctiva, orbit, larynx, lung, breast, kidney, liver, prostate, and even in the intracranial dura.53 5480 One-fourth of non-GI MALT lymphomas have been reported to present with involvement of multiple mucosal sites or nonmucosal sites such as bone marrow.53 54 Nevertheless, despite presenting so often with stage IV disease, they usually have a quite indolent course regardless of treatment type (5-year survival of 90 ). The rate of histologic transformation seems much lower than that in follicular lymphomas. Patients at high risk according to the IPI, and those with lymph node involvement at presentation, but not those with involvement of multiple MALT sites, have a worse outcome. Localization may have prognostic relevance. In a radiotherapy study from Toronto,70 gastric and thyroid MALT lymphomas had better...

Biology and Pathology

In the adult setting, each organ site is usually affected by one predominant histological type of cancer (e.g., in the kidney, RCC in the bladder, TCC in the prostate, adenocarcinoma). However, other histological types are also diagnosed, although less commonly small-cell carcinoma may occur in the bladder, cervix, and prostate collecting-duct tumors may occur in the kidney lymphomas and sarcomas are also infrequently diagnosed. The pattern of histologies seen in the adult setting is presumably in part due to the result of exposure to prevalent carcinogenic agents and one would therefore predict that a different profile of histologies might be seen in teenagers and young adults. This is difficult to confirm given the very small numbers in any of the reported series, but there is a general impression that a wider or more even spectrum of histology is seen in the very young adults with cancer in the genitourinary system.

Hyaluronan in Adhesion Migration and Invasion of Cancer

In cancers such as prostate cancer, which specifically metastasise to the bone, the circulating tumour cells undergo an adhesion process to the endothelial cells lining the bone marrow vasculature (54) followed by transmigration through the endothelial cell barrier and subsequent establishment in the stroma. Interestingly, HA has already been shown in murine anterior prostate gland to be a prerequisite for androgen stimulated ductal branching morphogenesis (55). Further to this, the role of HA in prostate cancer cell adhesion to bone marrow derived endothelial cell line (BMEC-1) has been demonstrated (56). In this study, highly metastatic PC3 and PC3M-LN4 showed a rapid adherence to BMEC-1 but not to endothelial cells derived from human vein. Adhesion was inhibited by the addition of excess HA or by pre-treatment of cells with hyaluronidase which digested away pericellular HA. Of note, pericellular HA was also correlated with increased level of HA synthesis and HA synthase expression...

Hyaluronan and Angiogenesis

A key aspect of tumour establishment and growth involves angiogenesis. Without neovascularization, essential nutrients cannot be supplied to solid tumours, preventing their ability to proliferate, invade or metastasise. HA has been shown to have an important role in vasculature and the angiogenic process (48,82). West and Kumar (83) first showed that HA oligosaccharides increased angiogenesis and that administration of high MW HA inhibited this process (82). This may appear paradoxical to findings that show the production of high MW HA by HAS (84) is correlated to tumour progression, and that inhibition of HAS reduced prostate tumour vascularity (85). More recently, some of the key intermediates such as the tyrosine phosphorylation and membrane recruitment of PLC-g 1 were shown to be activated in bovine aortic endothelial cells by HA oligos (86). There is little doubt that the involvement of HA in the angiogenic process is complex and requires further work for clarification. However,...

Effectiveness Of Allogeneic Wholecell Vaccination

Proof of principle for the effectiveness of allogeneic whole-cell vaccination has been established in mouse tumor models where both prophylactic protection against tumor challenge and the presence of tumor-specific CTLs was demonstrated 22,26,27 . In a rat Lobund-Wistar model of prostate cancer, prophylactic vaccination with an allogeneic cell vaccine was effective in protecting 80 of the treatment group against challenge with a PAIII tumor 28 . When this was repeated in a Copenhagen rat model (where the cancer was poorly immunogenic and more aggressive), no protection was elicited by treatment with allogeneic vaccine. However, this and other studies have shown that addition of adjuvant to ineffective allogeneic vaccines leads to protection against tumor challenge 27,28 . Clinical trials have been quick to follow, and while encouraging clinical results have been shown in melanoma and prostate cancer, there remain difficulties in monitoring immunologic responses to such vaccines....

Hypothesis of Melatonin

One possible interaction hypothesis under investigation is that exposure to EM fields suppresses the production of melatonin, which is a hormone produced by the pineal gland, a small pinecone-shaped gland located deep near the center of the brain. Melatonin is produced mainly at night and released into the blood stream to be dispersed throughout the body. It surges into almost every cell in the human body, destroying free radicals and helping cell division to take place with undamaged DNA. Melatonin also assists in regulating the female menstrual cycle and circa-dian rhythms. Melatonin secretion decreases over a lifetime, peaking in childhood and gradually lessening after puberty. Usually, people over 60 secrete far less than they do when young. Also, melatonin regulates sleep, mood, behavior, and gene expression. It reduces secretion of tumor-promoting hormones. It has the ability to increase cytotoxicity of the immune system's killer lymphocytes therefore, its production is...

Modification Of Allogeneic Vaccines To Secrete Cytokines

In clinical trials a GM-CSF-secreting allogeneic vaccine composed of two pancreatic cell lines (PANC-10.05 and-6.03) exhibited a trend toward disease free survival in patients with pancreatic adenocarcinoma, although patient numbers were too small to make this study statistically significant 76 . More recent studies have used a combination of GM-CSF-secreting cells (PC-3 and LNCaP) for the treatment of advanced hormone-resistant prostate cancer. Presentations at ASCO suggest that in 7 of 10 patients there was a trend toward increased survival 77 . Several other phase I II trials using this allogeneic vaccine are ongoing for prostate cancer.

Metastatic Tumours and Tumours from Neighbouring Sites

A wide variety of tumours can invade the orbit and produce proptosis and often diplopia. Lymphoma is one example. It can present as an isolated lesion or in association with Hodgkin's disease or leukaemia. Examples of local spread from adjacent structures include carcinoma of the nasopharynx, carcinoma of the lacrimal gland and meningioma. In children, orbital metastases arise most commonly from neuro-blastoma and Ewing's sarcoma. In the adult, the commonest primary sites are bronchus, breast, prostate and kidneys.

Pyrazoles and Pyrazolones

Pound 71 was selective against 56 kinases (IC50 > 1 M) but was an inhibitor of FLT-3 (IC50 0.03 M), Fyn (IC50 0.52 M), ITK (iC50 0.22 M), Lck (IC50 0.08 M), and Src kinases (IC50 0.35 M). The compound inhibited the phosphorylation of Histone-H3 in MCF7 cells at concentrations of 0.003-0.3 M and blocked tumor cell proliferation in a wide panel of tumor cell lines (colorectal, leukemia, breast, prostate, pancreatic, melanoma, cervical) with EC50 values ranging from 0.015 to 0.113 M. In MCF7 cells 71 induced polyploidy in cells with 4N DNA content. Compound 71 inhibited HeLa cell division however, these cells were still able to enter mitosis and proceed through S-phase. Compound 71 had no effect on the viability of non-cycling cells or peripheral blood mononuclear cells at concentrations up to 10 M. The inhibitor promoted a dose-proportional inhibition of tumor growth in in vivo human xenograft tumor studies in nude mice following either intraperitoneal or intravenous administration in...

Monoclonal Antibody And Endocrine Therapy For Breast Cancer And Tumor Immunity

Cetuximab is a humanized monoclonal antibody specific for the epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase receptor over-expressed by a variety of epithelial tumors, including colorectal, aerodigestive, prostate, ovarian, and breast cancers. Notably, the EGFR protein has emerged as a prominent molecular feature of the basal-like subset of breast cancers. This breast cancer subset is triple negative that is, it does not express the estrogen receptor (ER), the progesterone receptor (PR), or HER2 neu. Therefore, no targeted therapies exist to complement chemotherapy for the treatment of this breast cancer subtype, and it poses an unmet medical need. Like trastuzumab, cetuximab inhibits the signaling pathways that promote tumor growth and progression, and also induces tumor apoptosis. In particular, cetuximab can synergize with PTX to reduce angiogenesis and induce tumor cell apoptosis 54 . Immunomodulatory activity for cetuximab has not been reported. ovarian...

Biomarkers And Signatures

Carcinogenic potential is conventionally measured using a two-year study, incurring significant expense in both animals and human resources. It is therefore of great interest to identify biomarkers of carcinogenicity that can be detected in acute, short-term studies, and efforts toward this have been reported 36,40,58-60,88 . Biomarkers with clinical relevance have also been found using toxicogenomics approaches. For example, Petricoin et al. 89 found a set of protein markers that distinguished patients with high levels of prostate-specific antigen (PSA), a clinical marker correlated with prostate cancer, from those with low PSA levels and thus presumed to be healthy. In addition the marker set also correctly predicted 71 of patients with intermediate PSA levels. In a second example 90 , three plasma biomarkers were discovered and then independently validated to detect early stage invasive epithelial ovarian cancer from healthy controls with high sensitivity and specificity compared...

The Great Cancer Myths

In most polls, it is the most feared disease of all. Coupled with this are the almost daily media reports of another carcinogen or cancer risk being found in our environment that produce a setting for the sometimes hysterical fear that cancer lurks around every corner. Epidemiological pronouncements that one out of eight women will die of breast cancer or one of every four men will get prostate cancer, while perhaps having some statistical validity if everyone would reach age 80 and die of nothing else, belies the real risk of getting and dying of cancer. A study published by Wo-loshin et al.151 puts this rate in a more rational context. never smoked, 14 of 1000 will die of heart disease, 5 of lung cancer, and 7 of breast cancer by the time they reach 70 years of age. For 60-year-old men who are smokers, 84 of 1000 will die of heart disease and 98 of lung cancer, but only 4 of 1000 will die of prostate cancer.

Immunotherapy Approaches

MICA was the first NK receptor ligand that was found to be shed during tumor development. MICA is commonly expressed on multiple tumor types of epithelial origin, including gastrointestinal, lung, breast, kidney, ovary, prostate, colon, and hemato-poietic malignancies. The mechanism of MICA shedding is dependent on metallo-proteinases (Salih et al, 2002). Use of a matrix metalloproteinase inhibitor (MMPI) prevented MICA shedding and led to the accumulation of ligands on the cell surface, while a serine protease inhibitor had no effect.

Polycomb And Trithorax Gene Families Contain Epigenetic Modifiers Commonly Altered In Human Cancers

Capable of cooperating with the MYC oncogene to transform mammalian cells 34 . BMI-1 is frequently overexpressed in human cancer, an effect critical for maintaining the high proliferative rate of tumor cells 35 . Additionally, EZH2 is overexpressed in both epithelial tumors and in human prostate cancer 36 .

Tumours as Source of PIF

The 24-kDa factor was initially isolated from the murine cachexia-inducing MAC16 tumour 11 , but it was also found to be present in the urine of patients with carcinoma of the pancreas, breast, ovary, lung, colon, rectum, and liver in whom the rate of weight loss was > to about 1 kg per month 16 . Patients who were weight-stable or in whom the rate of weight loss was < 1 kg month showed no evidence for excretion, even though they had the same tumour types. Subjects with weight loss associated with conditions other than cancer, such as sepsis, multiple injuries, major surgery, and sleeping sickness, showed no evidence for urinary secretion of the 24-kDa material, even though the rate of weight loss was higher than in cancer patients. Immunohistochemistry with the MAC16 monoclonal antibody showed that the 24-kDa material was present in the cytoplasm of tumours of the gastrointestinal tract, and a correlation was obtained between expression in tumours, detection in urine, and weight...

Posttranslational Modification Of Nonhistone Proteins Involved In Cancer

Posttranslational modifications such as those mentioned earlier do not occur exclusively upon DNA. Protein acetylation, phosphorylation, and ubiquitination are as common as they are important, resulting in drastic changes in a cell's state following even a single epigenetic event. It is this ability to exponentially influence signaling within a cell system through modification of key proteins at the crossroads of signal transduction networks that showcases the power and significance of epigenetic events. Herein, we explore this phenomenon by focusing on how epigenetic events that alter nuclear receptors (NRs) in breast and prostate cancer. These NR transcription factors (TFs) undergo numerous posttranslational modifications elicited by coregulator proteins such as methyltransferases, kinases, phosphatases, acetyltransferases, and deacetylases. As a result, these modifications are sufficient to alter and modulate a receptor's abundance, activity, and ability to interact with binding...

Expression of Mtmmp Genes in Tissues

The expression of MT-MMPs is differentially controlled at the transcriptional level as evident from the tissue distribution of their mRNAs (Puente et al., 1996 Shofuda etal., 1997 Takino etal., 1995a,b Will and Hinzmann, 1995). In contrast to most secreted members of the MMP family, the mRNAs for the six MT-MMPs are detectable in the extracts of many tissues and varies considerably (Table I). Northern blot analysis revealed MT1-MMP in adult human intestine, kidney, lung, ovary, placenta, prostate, and spleen (Will and Hinzmann, 1995). MT2-MMP is expressed in colon, heart, brain, intestines, pancreas, and testis, and less in the lung, kidney, spleen, liver, and muscle (Seiki, 1999). MT3-MMP is expressed in human placenta, ovary, brain, lung, and vascular smooth muscle cells (Shimada et al., 1999). MT4-MMP is localized in brain, colon, ovary, testis, leukocytes, and in a variety of transformed cell types (Grant et al., 1999 Puente et al., 1996). MT5-MMP is expressed in brain, kidney,...

Suppression of Autoimmune Disease by Regulatory Cells from Donors with or Without the Relevant SelfAg

In view of differential suppression of autoimmune prostatitis (AIP) and autoimmune thyroiditis by T cells from Ag-positive vs Ag-negative cell donors (described below), how do we explain their equal suppression of AOD Our interpretation is that even if the regulatory capacities of male and female CD4+CD25+ T cells for AOD suppression are different, they are equalized when the cells encounter the endogenous ovarian Ag in the young d3tx host. Indeed, we have shown that ovarian Ags (mater and ZP3) are expressed from birth and have the capacity to stimulate T cells on day 3 (Alard et al. 2001). This is also exemplified by the process of diversified autoAb response that depends on de novo B cell response to endogenous ovarian Ag. Immunized female mice with a ZP3 peptide that contains T but not native B epitope (in CFA) elicited Ab response to a distant native ZP3 B cell epitope within 7 days, 2 days after detectable response to the ZP3 T cell epitope (Lou et al. 1996). Other examples of...

Gastrointestinal and Respiratory Epithelium

Figure 2 Hyaluronan in glandular epithelia. Hyaluronan in bovine tissues was visualized using bHABC and avidin biotin-peroxidase technique using DAB as a chromogen. (a) Sublingual gland, (b) lacrimal gland, (c) prostate, (d) seminal vesicle, (e) Cowper's gland, (f) epididymis. Arrows indicate the location of hyaluronan in the glandular epithelial tissues (a-e), while in the epididymis the staining intensity is lower and localized around the basal cells. The arrowhead in (a) indicates mucous glands, which are devoid of hyaluronan. The asterisk in (d) indicates secretion inside the gland, showing intense staining with bHABC. Figure 2 Hyaluronan in glandular epithelia. Hyaluronan in bovine tissues was visualized using bHABC and avidin biotin-peroxidase technique using DAB as a chromogen. (a) Sublingual gland, (b) lacrimal gland, (c) prostate, (d) seminal vesicle, (e) Cowper's gland, (f) epididymis. Arrows indicate the location of hyaluronan in the glandular epithelial tissues (a-e),...

Genital and Urinary Tracts and Mesothelial Cells as Hyaluronan Producers

The expression of hyaluronan in the simple epithelia of the male reproductive tract and its accessory glands is more active than that in the gut and intestine. Distal epididymis, vas deferens, seminal vesicle, prostate, and Cowper's gland show hyaluronan located mainly on the lower basolateral surface, but with little on the apical surface (Fig. 2c-f) (38). In these epithelia, the location of CD44 correlates with that of hyaluronan on the basolateral surfaces. This distribution suggests that hyaluronan is mostly synthesized and remains bound on the basal side of the adjacent epithelial cells. However, the lumen of the seminal vesicle, prostate and Cowper's gland (Fig. 2c-e) contain hyaluronan, suggesting that it is either secreted from the apical surface, or passes the cell junctions in the lateral sides of the cells. There is an extensive pool of hyaluronan in the underlying stroma of these glands, a potential source of the epithelial and lumenal hyaluronan. Interestingly, testis...