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)

Two hundred and nine patients with biopsy-proven stage D2 prostatic carcinoma showing disease progression after orchiectomy or treatment with DES (stilboestrol) or an LHRH agonist alone received combination therapy with the pure antiandrogen flutamide. In patients treated with DES, the oestrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide. The objective response to therapy was assessed according to the criteria of the US NPCP. Thirteen patients had a complete response to treatment, while partial and stable responses were achieved in 20 and 39 patients respectively (total objective response rate of 34.5%). The mean duration of response was 24 months. In the non-responders the median survival was 8.1 months with a 17% probability of survival at 2 years; the probabilities of survival at 2 years of the patients who showed partial and stable responses were 87 and 67% respectively. All patients who achieved a complete response are still alive. Combination therapy with Flutamide and castration (surgical or LHRH agonist) appears to be the treatment of choice for prostate cancer patients in relapse after standard endocrine therapy.
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PMID:Benefits of combination therapy with flutamide in patients relapsing after castration. 275 68

Sixty-seven previously untreated patients presenting with clinical stage C prostatic carcinoma with no evidence of distant metastases received combination therapy using the antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average duration of treatment of 23.5 months. Only five patients have so far shown treatment failure with 91.8% of the patients still in remission at 2 years. Three patients have died from prostate cancer while three have died from other causes, 93.5% of the patients being alive at 2 years. Local control was achieved rapidly in all except one patient. Urinary obstruction and hydronephrosis were corrected in all cases. When comparing to recent data obtained after single endocrine therapy (orchiectomy or estrogens), or radiotherapy, the rate of treatment failure at 2 years is 3.5-fold lower after combination therapy (8.2%) than monotherapy (28.4%). The death rate at 2 years following start of the combination therapy is 6.5% while it is on average 22.2% (3.4-fold higher) in the studies using monotherapy (orchiectomy or estrogens) or radiotherapy. The present data suggest that treatment of prostate cancer with combination therapy before clinical evidence of dissemination of the disease permits a better response which is possibly explained, at least in part, by the lower degree of dedifferentiation and heterogeneity of the tumors.
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PMID:Combination therapy with flutamide and [D-Trp6]LHRH ethylamide for stage C prostatic carcinoma. 328 45

One hundred and ninety-nine patients with clinical stage D2 prostate cancer who had not received previous endocrine therapy or chemotherapy were treated with the combination therapy using the pure antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average of 26 months (3-59 months). The objective response to the treatment was assessed according to the criteria of the U.S. NPCP. There was a 5.7-fold increase (26.3 vs 4.6%) in the percentage of patients who achieved a complete response compared with the results obtained in five recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 12 of the 186 evaluable patients (6.5%) did not show an objective positive response at the start of the combination therapy compared with an average of 18% in the same five studies using monotherapy. The duration of response was also significantly improved in the patients who received the combination therapy while the death rate was decreased by approximately two-fold during the first 4 yr of treatment. In fact, while an approximately 50% death rate is observed at 2 yr in all studies using monotherapy, the same 50% death rate is delayed by 2 yr in the present study. It should be mentioned that at the time of relapse under combination therapy, the treatment is continued and, in addition, further blockade of adrenal androgen secretion is achieved with aminoglutethimide. The marked (5.7-fold) improvement in the rate of complete objective responses coupled with the three-fold decrease in the number of non-responders, the increased duration of the positive responses and the two-fold decrease in the death rate during the first 4 yr of treatment are obtained with the combination therapy using Flutamide and castration, thus improving the quality and duration of life with no or minimal side-effects. By blocking the androgen receptors in the prostatic cancer tissue, the antiandrogen decreases the action of the androgens of adrenal origin and thus inhibits the growth of a large number of tumors which, otherwise, would continue to be stimulated by the adrenal androgens left after medical or surgical castration.
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PMID:Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in previously untreated patients with clinical stage D2 prostate cancer: today's therapy of choice. 329 May 78

In 1941, Huggins and his colleagues discovered that testicular androgens exert a stimulatory effect on prostate cancer growth. Our group has made the key observations that the human adrenals, in addition to the tests, also secrete important amounts of androgens and cancer cells exhibit a marked heterogeneity of androgen sensitivity. In fact, human adrenals secrete large amounts of precursor steroids that are converted into active androgens in peripheral tissues (including the prostate), thus providing 40% to 50% of total androgens in adult men. The action of these androgens remaining after castration can be inhibited in prostatic cancer tissue by administering a pure antiandrogen that also decreases the local concentration of dihydrotestosterone (DHT). The castration levels of serum testosterone left in men after castration have an important stimulatory activity on the growth of androgen-sensitive normal as well as cancer tissues. Cancer cells have markedly different requirements for androgens. Some cell clones can grow in the presence of minimal amounts of androgens, requiring more complete androgen blockade and more potent antiandrogens for inhibiting growth. Among the compounds recommended as antiandrogens, the most unexpected finding is that many of them are devoid of any antiandrogenic activity. In fact, medroxyprogesterone acetate, chlormadinone acetate, and megestrol acetate have androgenic activity, but do not inhibit the peripheral action of DHT in prostatic tissue. These compounds should not be classified as antiandrogens. Cyproterone acetate, on the other hand, is a mixed agonist-antagonist. The only compounds showing pure antiandrogenic activity are Flutamide and its analogues. There is thus a need for a more complete blockade of androgens of both testicular and adrenal origins in order to exert a maximal inhibitory effect on cancer growth. We have therefore performed clinical studies in previously untreated stage D2 and C prostate cancer patients with the combination therapy using the LHRH agonist [D-Trp6, des Gly NH2(10)] LHRH ethylamide and the antiandrogen Flutamide. There was a significant increase in patients with a complete response, as compared with studies limited to the removal or blockade of testicular androgens. There was also a significant decrease in the number of non-responders, an increased duration of positive response, and a decrease in the death rate. This was achieved with minimal or no side effects, thus preserving a good quality of life.
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PMID:Combination therapy in stage C and D prostatic cancer: rationale and five year clinical experience. 332 35

It is now well established that chronic treatment with GnRH agonists offers an advantageous alternative to orchiectomy and estrogens for the treatment of prostate cancer. Castration levels of androgens can thus be easily achieved without side effects other than those related to castration levels of serum androgens. However, man is unique among species in having a high secretion rate of precursor adrenal steroids which are converted into active androgens in the normal prostate and prostatic cancer. All the enzymes required for the transformation of dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and androst-5-ene-3 beta, 17 beta-diol are present in prostatic tissue. Moreover, as shown in many systems, castration levels of serum testosterone (T) at 0.2-0.4 ng/ml exert significant androgenic activity in target tissues. In order to inhibit the action of androgens of both testicular and adrenal origin, GnRH agonists have been administered in association with the pure antiandrogen Flutamide in patients having clinical stage D2 (bone metastases) prostate cancer. A positive objective response assessed according to the criteria of the United States National Prostatic Cancer Project (USNPCP) has been observed in 84 of the 88 patients who had received no previous treatment (95.4%). After 2 yr of treatment, the probability of continuing response is 70% compared to 0-10% by previous approaches. In addition, the death rate at 2 yr is at 10.9% as compared to approximately 50% after standard hormonal therapy. When the same treatment was applied to patients who had received previous hormonal therapy (orchiectomy, estrogens or GnRH agonists alone) before showing a relapse, the response rate decreased to 62.9% and the death rate at 2 yr was 52%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment of prostate cancer with gonadotropin-releasing hormone agonists. 351 3

Beside orchiectomy and estrogens, other endocrine manipulations are proposed for metastatic prostatic cancer patients. Antiandrogens, Cyproterone acetate and Flutamide, are often less efficient but less toxic than DES. Progestational agents medroxyprogesterone acetate, megoestrol acetate, chlormadinone acetate have also a limited activity. Inversely, tamoxifen is very little active. Preliminary results of ketoconazole need more controls. The present aims are to obtain, particularly by hormonal association, a more efficient and less toxic treatment, when DES can be given initially or becomes inefficient.
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PMID:[Cancer of the prostate: new hormone therapies]. 377 22

As has been clearly demonstrated in prostate and breast cancer, progression to hormone insensitivity is a major problem responsible for the usually partial and short-lived response to antihormonal therapy. Preincubation of androgen-sensitive Shionogi mouse carcinoma cells for 15 days in the absence of androgens causes the development of complete resistance of cell growth to androgens. Of potentially important therapeutic significance is the finding that androgen sensitivity can be maintained not only by the androgen dihydrotestosterone (DHT) but also by incubation with the pure antiandrogen Flutamide-OH in the absence of androgens. Since androgen resistance is one of the main problems facing the treatment of prostate cancer, the possibility of avoiding or at least delaying the development of androgen resistance with a pure antiandrogen could well provide the basis for improving the success of therapy for this disease.
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PMID:Development of androgen resistance in mouse mammary tumor cells can be prevented by the antiandrogen flutamide. 382 19

Seventy-two patients with advanced prostatic carcinoma without previous endocrine therapy were treated with an oral nonsteroidal antiandrogen, flutamide. Sixty-three patients (87.5%) had a favorable response, and 9 patients showed no response. Flutamide appears to be a safe antiandrogen, usually effective in the management of patients with advanced prostatic cancer who have had no prior endocrine therapy.
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PMID:Experience with flutamide in patients with advanced prostatic cancer without prior endocrine therapy. 637 56

Difluoromethylornithine (DFMO) and methylglyoxal-bis(guanyl-hydrazone) (MGBG), inhibitors of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AMDC), respectively, were tested in two experimental prostatic cancer models. DFMO resulted in a reduction in tumor size in both the rapidly growing R-3327 rat prostatic adenocarcinoma (30.5 +/- 15 versus 61 +/- 9.5 in control animals) and the human DU-145 adenocarcinomas (1.7 ml versus 3.3 ml in control animals) in nude mice. MGBG was tested only in the rat tumor, where it induced a reduction of 22.9 +/- 9.5 ml versus 61 +/- 9.5 in control animals in tumor size but was highly toxic. Flutamide or 9-B-D-arabinofuranosyladenine (Ara-A) proved ineffective per se in reducing tumor growth of the human DU-145 or of the R-3327-G strain, respectively, but increased the efficacy of DFMO against the DU-145 tumor had a high level of ODC which was reduced by DFMO of by Ara-A; the R-3327 tumor had a low level of ODC which was too low to be decreased by DFMO.
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PMID:Some effects of inhibitors of polyamine synthesis on experimental prostatic cancer. 642 51

Flutamide, a new non-steroidal antiandrogenic agent, was administered in the treatment of five assessable patients with advanced carcinoma of the prostate. Two patients showed significant clinical benefit, one showed a reduction in his requirement for analgesia and two failed to benefit; side-effects were minimal. These results indicate the need for a controlled clinical trial of flutamide in patients with prostatic cancer.
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PMID:A pilot study of flutamide. A new agent in the treatment of advanced prostatic cancer. 669 25


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