Rationale for the Use of 5aReductase Inhibitors in Cancer Treatment

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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 genitalia, increases the muscle mass, deepens the voice, and affects spermatogenesis, sexual potency and male sexual behaviour. DHT is responsible for the increase of body hair and facial hair and the enlargement of the prostate. The abnormal production of DHT has been associated with diseases of the prostate and the skin, and high interest has been paid to the synthesis of 5a-reductase inhibitors for the treatment of DHT-related pathologies. Further evidence for a role of the 5aR-2 in the pathogenesis of DHT-related disorders comes from the clinical phenotype of 5aR-2 deficiency. In individuals with a total deficiency of 5aR-2, the prostate remains undeveloped, facial and body hair growth patterns are more feminine in character, and the temporal regression of the hair line is significantly reduced, indicating that 5aR-2 is involved in prostatic diseases and to some extent in androgenic alopecia [116]. For this reason, the development of 5aR-2-specific inhibitors for the treatment of DHT-dependent pathologies has been a major focus of pharmaceutical research.

Whether the selective inhibition of 5aR-2 may provide an advantage over inhibition of both 5a R-2 and 5aR-1, will have to be shown by comparing finasteride (rather type 2-selective) and dutasteride (a type 1 and type 2 inhibitor) (Fig. 10). At present, no selective 5aR-1 inhibitor is available for the

NADPH NADP+

NADPH NADP+

Testosterone

5a-Dihydrotestosterone

Testosterone

Finasteride

Finasteride

5a-Dihydrotestosterone

Dutasteride

Dutasteride o N u

Turosteride

Turosteride

LY-191704

LY-191704

Fig. 10 A Enzymatic mechanism of 5a-reductase and B structures of 5a-reductase inhibitors treatment of 5aR-1-related pathologies but pharmaceutical research is active in this field [117].

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