|
|
|
Hair Loss Study Abstract: P450-dependent enzymes as targets for prostate cancer therapy.
|
Title
P450-dependent enzymes as targets for prostate cancer therapy.
Author
De Coster R; Wouters W; Bruynseels J
Address
Janssen Reserach Foundation, Beerse, Belgium.
Source
J Steroid Biochem Mol Biol, 56: 1-6 Spec No, 1996 Jan, 133-43
Abstract
Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among
men. First line treatment is primarily aimed at blocking the synthesis and action of
androgens. As primary endocrine treatment, androgen deprivation is usually achieved by
orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in
order to block the residual adrenal androgens. However, nearly all the patients will
eventually relapse. Available or potential second line therapies include, among others,
alternative endocrine manipulations and chemotherapy. Cytochrome P450-dependent enzymes
are involved in the synthesis and/or degradation of many endogenous compounds, such as
steroids and retinoic acid. Some of these enzymes represent suitable targets for the
treatment of prostate cancer. In first line therapy, inhibitors of the P450-dependent
17,20-lyase may achieve a maximal androgen ablation with a single drug treatment.
Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its
side-effects, mainly gastric discomfort, limit its widespread use. A series of newly
synthesized, more selective, steroidal 17,20-lyase inhibitors related to
17-(3-pyridyl)androsta-5,16-dien-3beta-ol, may open new perspectives in this field. In
prostate cancer patients who relapse after surgical or medical castration, therapies
aiming at suppressing the remaining adrenal androgen biosynthesis (ketoconazole) or
producing a medical 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 aminoglutethimide, could not be confirmed by the use of more selective
aromatase inhibitors, such as formestane. An alternative approach is represented by
liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic
acid (RA). In vitro, it enhances the antiproliferative and differentiation effects of RA
in cell lines that express RA metabolism, such as F9 teratocarcinoma and MCF-7 breast
carcinoma cells. In vivo, monotherapy with LIA increases RA plasma levels and, to a
greater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the
rat Dunning prostate cancer models, it inhibits the growth of androgen-independent as well
as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the
pattern of cytokeratins 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 unselected patients. In some patients
regression of soft tissue metastasis ha been observed. In a subgroup of patients, an
important relief of metastatic bone pain was also noted.
Language of Publication
English
Unique Identifier
96184197
content2 |
|
