Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ketoconazole is an orally active antimycotic agent and a potent inhibitor of gonadal and adrenal steroidogenesis. As inhibitor of steroid production, it has been employed in Cushing's syndrome, prostatic cancer and precocious puberty due to autonomous Leydig-cell hyperfunction. By virtue of its selective action on androgen synthesis at low doses by inhibition of C17-20 lyase, this drug could be of potential therapeutic utility in hirsutism. We evaluated the hormonal and clinical effects of a low-dose regimen (400 mg/day) for 3 months in 16 women with a spectrum of disorders from idiopathic hirsutism to polycystic ovary syndrome. Four of them completed 6-month treatment. At 3 months, DHEA-S decreased from 9.9 +/- 1.0 (mean +/- SE) to 6.9 +/- 1.0 mumol/L (p less than 0.01), androstenedione from 13.3 +/- 1.5 to 8.3 +/- 1.3 nmol/L (p less than 0.005), and testosterone from 4.2 +/- 0.4 to 3.1 +/- 0.4 nmol/L (p less than 0.05). No significant changes were observed in LH, FSH, prolactin and estradiol levels. In patients treated for 6 months, androgens were within normal limits at the end of the study. Eleven out of 16 women (about 70%) reported some improvement in their hirsutism. There was a significant decrease in Ferriman-Gallwey's score (p less than 0.001) and mean hair-shaft diameter (p less than 0.001). The patients treated for 6 months showed a further improvement. Pelvic ultrasonography, when repeated (n = 8), was either unchanged or improved. Side effects (polymenorrhea, gastrointestinal reaction, somnolence) were generally mild and transient. Of 20 women who entered the study the dropout rate was 20% (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Low-dose ketoconazole treatment in hirsute women. 213 47

Newer methods of androgen ablation for the treatment of metastatic prostatic carcinoma have been developed as alternatives to the standard forms of therapy, oral estrogens and surgical castration. The purpose of this review is to elucidate the indications and to determine the role of ketoconazole in the management of metastatic prostatic cancer. Eighteen patients have been treated with ketoconazole. The indications for usage have included: prompt therapeutic response, when orchiectomy is contraindicated, when estrogens are contraindicated, initial empirical therapy, and hormonally refractory disease. It can also be used in conjunction with luteinizing hormone-releasing hormone analogues. Ketoconazole is excellent for short-term usage prior to bilateral orchiectomy and when prompt therapeutic response is needed but orchiectomy cannot be performed. However, it is not particularly useful for long-term hormonal therapy.
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PMID:Indications for use of ketoconazole in management of metastatic prostate cancer. 224 27

Several exciting new forms of therapy for metastatic prostatic cancer have been introduced recently. Luteinizing hormone-releasing hormone (LH-RH) agonists paradoxically inhibit pituitary release of luteinizing hormone, resulting in a fall of serum testosterone to castrate levels within two to four weeks. These drugs have no cardiovascular side effects. A nonsteroidal antiandrogen, flutamide, may be as effective as orchiectomy in men with untreated metastatic disease and has the advantage of preserving potency in most men. In recent reports, combining the LH-RH agonist with an antiandrogen resulted in "total medical castration," which may substantially improve objective response rates and patient survival. Ketoconazole, an antifungal drug, also rapidly inhibits testicular and adrenal androgen synthesis and decreases plasma testosterone to castrate levels within 72 hours. In men with hormone-resistant disease, combination chemotherapy may produce an objective response rate of 50%. In men with severely painful bony metastasis, an inexpensive drug used in Paget's disease, etidronate disodium, may be palliative.
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PMID:Advances in the treatment of metastatic prostatic cancer. 241 32

The antifungal drug ketoconazole has been shown to block testosterone synthesis. High dose ketoconazole therapy was given to 17 patients with previously untreated stage D2 prostatic cancer. Rapid relief of pain occurred in 15 patients with significant pain. Prostatic acid phosphatase levels normalized or decreased in all patients. Bone scan scores were stable or improved. Two patients remain on therapy for more than 30 months. The remainder have ceased treatment owing to subsequent progressive disease (5 patients), side effects (6) or noncompliance. Eleven patients who had relapse after previous endocrine ablative therapy were treated with ketoconazole. Subjective responses were frequent but long-term objective responses were rare. There was a high incidence of side effects, particularly nausea. Ketoconazole may have limited usefulness as initial therapy in patients with endocrine responsive advanced prostatic cancer. The drug can be palliative in some patients who have failed previous therapeutic modalities. Analogues of the drug should prove to have better efficacy and fewer side effects.
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PMID:Long-term experience with high dose ketoconazole therapy in patients with stage D2 prostatic carcinoma. 243 34

High-dose ketoconazole (400 mg orally three times a day) and physiologic replacement doses of glucocorticoids (hydrocortisone, 20 mg 8 AM, 10 mg 4 PM, and 8 PM) were administered to 38 patients with advanced prostatic cancer, refractory to at least initial testicular androgen deprivation. Thirty patients were completely evaluable; six were withdrawn due to possible ketoconazole-related toxicity and were considered drug failures. Two patients were unevaluable due to intercurrent therapy or inability to maintain follow-up. Ketoconazole was generally well tolerated. Mild or moderate nausea and vomiting occurred in 37% of patients, but required dose modification or discontinuation in only three patients; no hepatic damage was seen. Five of 36 patients (14%) responded to ketoconazole as determined by palpable or radiographic tumor mass reduction of 50% or greater and normalization of acid phosphatase or bone scan. Fifty percent of patients entered were stable at 90 days. Plasma androstenedione and dehydroepiandrosterone sulfate (DHEAS) were reduced markedly in almost all patients. Plasma testosterone (T) levels were low and remained unchanged, while gonadotropins were persistently elevated. Mean plasma ketoconazole content was 6.6 micrograms/mL after 28 days of therapy. While ketoconazole with hydrocortisone does suppress plasma androgens in advanced prostatic cancer patients, this infrequently causes regression of cancer that has progressed despite adequate testicular androgen ablation.
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PMID:High-dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects. 247 59

Forty-four patients who had metastatic cancer of the prostate that had not responded to conventional hormonal manipulation were treated with high-dose ketoconazole (600 to 1200 mg/d). All had castrate serum concentrations of testosterone prior to therapy. All patients had been categorized as having progressive cancer on assessment by the criteria of the National Prostatic Cancer Project. After treatment with ketoconazole, 57% were recategorized as having stable disease. The majority showed marked subjective lessening of pain on this therapy. Objective responses were noted but were not consistent. Side-effects were common but tolerable. The mean survival time was 73.3 weeks. Ketoconazole may be a useful palliative adjunct in the treatment of hormone-refractory prostatic cancer.
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PMID:Effects of high-dose ketoconazole on patients who have androgen-independent prostatic cancer. 247 37

Ketoconazole has been recently used in the primary treatment of patients with metastatic cancer of the prostate and is identified as a potent inhibitor of cytochrome P450-dependent adrenal and testicular androgen production. The drug has also shown activity in patients failing conventional hormonal manipulation. We subsequently showed that ketoconazole in vitro has a direct cytotoxic effect on human androgen-independent prostatic cancer cell lines. In order to better define the possible role of ketoconazole on hormone-independent prostatic cancer, we incubated the cells from human androgen-independent prostatic cancer lines in a methylcellulose tumour colony assay with different doses of the drug and increasing doses of conventional cytotoxic agents (etoposide, bleomycin, vinblastine, methotrexate, and teniposide). We demonstrated synergistic suppression of prostate cancer clonogenic cell growth by ketoconazole in the presence of vinblastine or etoposide. This observation may assign a new and important role for ketoconazole as part of combination chemotherapy in the treatment of patients with advanced prostatic cancer.
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PMID:Synergistic effect of ketoconazole and antineoplastic agents on hormone-independent prostatic cancer cells. 261 88

Ketoconazole high dose (H.D.) effectively reduces the testosterone production in both adrenals and testes. Its use in the management of (metastatic) prostate cancer has been advocated. Even in relapsing patients, after previous hormonal therapy, ketoconazole H.D. could be of value. Twenty-eight relapsing patients, of whom 15 were evaluable at three months, have been treated with ketoconazole H.D. As could be expected, objective response was seen in only a small number of patients followed up till nine months. Subjective improvement, however, was noticed in the majority of symptomatic patients. The side effects and toxicity of the therapy remain a major limitation for the use of ketoconazole, be it as first line treatment or as therapy for relapsing patients.
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PMID:Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer. Dutch South-Eastern Urological Cooperative Group. 265 64

Ketoconazole, an orally active antifungal drug, is known to inhibit testicular androgen production both in vitro and in vivo. The aim of the present study was to examine the effect of ketoconazole and 13 other imidazole drugs on rat testicular microsomal 17 alpha-hydroxylase, 17,20-lyase, 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) and 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR). The order of decreasing inhibitory effect (determined from Ki values) on 17 alpha-hydroxylase (substrate [3H]progesterone; Km = 89 +/- 0.65 nmol/l; SEM, n = 8) was bifonazole (Ki = 86 +/- 3.3 nmol/l; SEM, n = 4) greater than ketoconazole (160 +/- 4.92) greater than clotrimazole (170 +/- 5.81) greater than miconazole (599 +/- 7.22) greater than econazole (688 +/- 6.98) greater than tioconazole (901 +/- 1.71) greater than isoconazole (1090 +/- 6.96) and on 17,20-lyase (substrate, [3H]17 alpha-hydroxyprogesterone; Km = 250 +/- 0.75 nmol/l; SEM, n = 8) was bifonazole (56.5 +/- 3.4) greater than clotrimazole (81.5 +/- 3.1) greater than ketoconazole (84 +/- 3.5) greater than miconazole (243 +/- 6.3) greater than econazole (325 +/- 5.1) greater than tioconazole (505 +/- 5.2) greater than isoconazole (610 +/- 6.34). However, these imidazole drugs did not inhibit the 3 beta-HSD-I or 17 beta-HSOR activities. A common structural feature of the imidazole drugs having an inhibitory effect was the presence of one or more aromatic rings on the imidazole side chain. In contrast, the imidazole drugs having the imidazole ring fused to a benezene ring, i.e. benzimidazoles (astemizole, mebendazole, thiabendazole) and those having an aliphatic side chain on the N-1 of the imidazole ring (carbimazole, metronidazole, nimorazole, tinidazole) did not inhibit 17 alpha-hydroxylase, 3 beta-HSD-I or 17 beta-HSOR enzyme activities. However some did inhibit 17,20-lyase activity but only at high concentrations. The results of the present study suggest that some imidazole drugs may be useful in clinical situations requiring the suppression of androgen production, for example in the treatment of hormone-dependent prostatic cancer.
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PMID:Inhibition of testicular 17 alpha-hydroxylase and 17,20-lyase but not 3 beta-hydroxysteroid dehydrogenase-isomerase or 17 beta-hydroxysteroid oxidoreductase by ketoconazole and other imidazole drugs. 282 31

Ketoconazole has been recently used in the treatment of advanced prostatic cancer and is believed to exert its effect by inhibition of androgen production. In order to determine whether ketoconazole exerts an additional direct cytotoxic effect on prostate cancer cells, we studied its effect on human hormone-independent prostate cancer cell lines (PC-3 and DU-145) in an in vitro clonogenic tumor assay. We showed that clinically achievable doses of ketoconazole caused greater than 90% suppression of tumor colony growth.
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PMID:Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells. 290 48


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