High Doses of Dietary Antioxidants Enhance the Effect of Irradiation on Cancer Cells

Dietary antioxidants enhance the effect of irradiation selectively on cancer cells while protecting normal cells against some of the injuries. To observe this effect, antioxidants must be given before and after irradiation at high doses, and they must be present throughout the experimental period. The extent of enhancement of radiation damage by dietary antioxidant micronutrients depends upon the dose of radiation, dose and types of antioxi-dants, treatment period, and type of tumor cells.

Vitamin A, vitamin C, vitamin E, and caroten-oids under the above experimental conditions may protect normal cells against radiation damage, but may enhance the effect of irradiation on cancer cells. For example, retinoic acid enhances the effect of irradiation on tumor cells by inhibiting the repair of potential lethal damage in cancer cells more effectively than that produced in normal fibroblasts (59). Retinoic acid with interferon-a2a (lFN-a2a) enhances radiation-induced toxicity in neck and head squamous cell carcinoma cells in culture (60). We have reported that the dose of vi

GM2149 (normal human fibroblasts)

O Control

GM2149 (normal human fibroblasts)

O Control

Hours after adding colcemid

HeLa (human cervical carcinoma cells)

O Control

• Irradiation (1 Gy) 0.12H V 20 ^g/mL a-TS ▼ 20 ^g/mL a-TS + irradiation (1 Gy)

Hours after adding colcemid

HeLa (human cervical carcinoma cells)

O Control

• Irradiation (1 Gy) 0.12H V 20 ^g/mL a-TS ▼ 20 ^g/mL a-TS + irradiation (1 Gy)

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0123456789 10 Hours after adding colcemid

Fig. 11.2 Effect of a-TS on mitotic accumulation in human cancer cell lines and normal human fibroblasts. Decreased mitotic accumulation is seen in cancer cells, but not in normal fibroblasts. Each point represents an average of six samples. Significant difference at P = 0.05 was observed in all tumor cell lines at 20 mg/mL of a-TS at all points in comparison to controls (42).

0123456789 10 Hours after adding colcemid

Fig. 11.2 Effect of a-TS on mitotic accumulation in human cancer cell lines and normal human fibroblasts. Decreased mitotic accumulation is seen in cancer cells, but not in normal fibroblasts. Each point represents an average of six samples. Significant difference at P = 0.05 was observed in all tumor cell lines at 20 mg/mL of a-TS at all points in comparison to controls (42).

tamin E (a-TS) which inhibited the growth of human cervical cancer cells in culture, but not of normal human fibroblasts in culture, when given in a single high dose before irradiation, enhanced the levels of radiation-induced decrease in mitotic accumulation (Fig. 11.2) and chromosomal damage (Fig. 11.3) in cancer cells. This form of vitamin E was present in the growth medium before and after irradiation for the entire observation period. On the other hand, the same dose of a-TS did not modify the effect of irradiation on mitotic accumulation in normal cells (42), but it protected normal cells

Human tumor cell lines a 4

HeLa

OVGI

SKOV3

Human normal cell lines

GM2149

HF19

AG1522

GM2149

HF19

AG1522

Fig. 11.3 Effect of D-a-tocopheryl succinate (a-TS) on the level of radiation-induced chromosomal damage in human cervical cancer cells (HeLa), ovarian carcinoma cell lines (OVG1 and SKOV3), and in human normal skin fibroblasts (GM2149, HF19 and AG1522). D-a-tocopheryl succinate treatment alone increased chromosomal damage in all three cancer cell lines, but not in any normal cell lines. D-a-

tocopheryl succinate treatment also enhanced the levels of radiation-induced chromosomal damage in cancer cells but it protected normal cells against such damage. The bar is standard error of the mean; and the difference between control and experimental groups, and between irradiation alone and irradiation plus a-TS is significant at P = 0.05 (43).

Fig. 11.4 Neuroblastoma cells (NBP2) were plated in tissue culture dishes (60 mm), and the cells were y-irradiated 24 hours after plating. a-tocopheryl (a-TS) succinate or the solvent (ethanol 0.25 % and sodium succinate 5 ^g/mL) was added immediately before irradiation. The drugs and medium were changed after two days of treatment. The number of cells per dish was determined after three days of treatment. Each experiment was repeated at least twice involving three samples per treatment. The average value (172 ± 7 x 104) of untreated control NB cells was considered 100%, and the growth in treated cultures was expressed as a % of untreated controls. The bar at each point is standard error of the mean (61).

against chromosomal damage (43). In another study, we have reported that an aqueous form of a-tocopheryl and a-TS enhanced the level of radiation-induced growth inhibition in neuroblastoma (NB) cells (Fig. 11.4) (43, 61). Vitamin C enhanced the effect of irradiation on neuroblastoma (NB) cells, but not on glioma cells in culture (20). Dehy-droascorbic acid (DHA), the major metabolite of ascorbic acid, acts as a radiosensitizer for hypoxic tumor cells (62). These studies show that certain antioxidant micronutrients in a single high dose, when given before irradiation, can protect normal cells against some of the effects of radiation damage, as well as enhance the effect of irradiation on cancer cells in culture provided they are present throughout the experimental period. A similar observation has been made in an animal model. For example, vitamin A (retinyl palmitate) or p-caro-tene at high doses given daily through dietary supplement before x-ay irradiation and throughout the experimental period enhanced the levels of radiation damage on transplanted breast adenocar-cinoma in mice, and protected normal tissue against some of the toxicity of local irradiation (Table 11.4) (34). The administration of vitamin C through drinking water before and after roentgen ray irradiation decreased the survival of ascites tumor cells in mice without causing a similar effect on normal cells (63). The administration of multiple antioxidant micronutrients (vitamin A, vitamin C, and vitamin E) protected normal cells against damage produced by radioimmunotherapy in mice without protecting cancer cells (64). The doses of these multiple antioxidants may have been low; and therefore, the radiosensitizing effect of these micronutrients could not be observed. A few human studies have confirmed the differential modification of radiation injuries on normal and cancer cells by these antioxidants. For example, retinoic acid and IFN-a2a enhanced the efficacy of radiation therapy of locally advanced cervical cancer (36).

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