P450-DEPENDENT ENZYMES AS TARGETS FOR PROSTATE-CANCER THERAPY

Metastatic prostate adenocarcinoma is a leading cause of cancer-relate d deaths among men. First line treatment is primarily aimed at blockin g the synthesis and action of androgens. As primary endocrine treatmen t, androgen deprivation is usually achieved by orchidectomy or LHRH an alogues, frequently combined with androgen receptor antagonists in ord er to block the residual adrenal androgens. However, nearly all the pa tients will eventually relapse. Available or potential second line the rapies include, among others, alternative endocrine manipulations and chemotherapy. Cytochrome P450-dependent enzymes are involved in the sy nthesis and/or degradation of many endogenous compounds, such as stero ids and retinoic acid. Some of these enzymes represent suitable target s for the treatment of prostate cancer. In first line therapy, inhibit ors of the P450-dependent 17,20-lyase may achieve a maximal androgen a blation with a single drug treatment. Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its side-effect s, mainly gastric discomfort, limit its widespread use. A series of ne wly synthesized, more selective, steroidal 17,20-lyase inhibitors rela ted to 17-(3-pyridyl)androsta-5,16-dien-3 beta-ol, may open new perspe ctives in this field. In prostate cancer patients who relapse after su rgical or medical castration, therapies aiming at suppressing the rema ining adrenal androgen biosynthesis (ketoconazole) or producing a medi cal adrenalectomy (aminoglutethimide + hydrocortisone) have been used, but are becoming obsolete with the generalization of maximal androgen blockade in first line treatment. The role of inhibition of aromatase in prostate cancer therapy, which was postulated for aminoglutethimid e, could not be confirmed by the use of more selective aromatase inhib itors, such as formestane. An alternative approach is represented by l iarozole fumarate (LIA), a compound that blocks the P450-dependent cat abolism of retinoic acid (RA). In vitro, it enhances the antiprolifera tive and differentiation effects of RA in cell lines that express RA m etabolism, such as F9 teratocarcinoma and MCF-7 breast carcinoma cells . In vivo, monotherapy with LIA increases RA plasma levels and, to a g reater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the rat Dunning prostate cancer models, it inhibits the g rowth of androgen-independent as well as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the pattern of c ytokeratins characteristic of increased differentiation were observed. Early clinical trials show that LIA, in second or third line therapy in metastatic prostate cancer, induces PSA responses in about 30% of u nselected patients. In some patients regression of soft tissue metasta sis has been observed. In a subgroup of patients, an important relief of metastatic bone pain was also noted.