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)

The hormonal and clinical efficacy of (D-Leu6)-des Gly-NH2(10)-LH.RH ethylamide (Leuprolide, TAP 144) was investigated with 12 prostatic cancer patients. The hormonal studies were performed in 8 patients who were not previously treated by any hormonal therapies including estrogen, castration and others. Serum level of LH and FSH was apparently decreased at the end of 2 weeks after the starting of leuprolide (1 mg/day) subcutaneous injection. At the same time, testosterone level was decreased to the castration level. Clinical efficacy of 1 mg/day of leuprolide was evaluated in 7 patients who were not previously treated. Three of the 4 patients with stage B2 cancer showed a partial response and 1 patient a stable response; and 1 of the 3 patients with stage D2 cancer showed a partial response and patients stable a response. No significant side effects were observed in these 12 patients. These results show that 1 mg/day of leuprolide has the same degree of potency in decreasing the serum testosterone as 20 mg/day.
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PMID:[Hormonal and clinical efficacy of (D-Leu6)-des Gly-NH2(10)-LH.RH ethylamide against prostatic cancer]. 293 56

Luteinizing hormone-releasing hormone (LH X RH) agonist can be administered daily to patients with prostatic cancer with resulting clinical efficacy. A sustained drug release formulation of an LH X RH agonist, (D-Leu6)-des Gly-NH2(10)-LH X RH ethylamide (leuprolide)-vinyl polymer composite, was prepared by means of radiation-induced polymerization under a supercooled state. The sustained release of leuprolide from subcutaneously implanted leuprolide-vinyl polymer composite (14 mm in diameter and 4 mm in thickness) was obtained over a period of several months in five patients with prostatic cancer. Serum testosterone levels began to decrease on the tenth day, fell below 1 ng/ml after three weeks of implantation, and thereafter remained at the castration level until removal of the polymer composite. Clinical improvement was associated with serum hormonal changes, and support this as a novel and superior method of administration of LH X RH agonist.
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PMID:The sustained release of LH X RH agonist from LH X RH agonist-polymer composite in patients with prostatic cancer. 308 53

One hundred and eighty-six previously untreated patients with clinical stage D2 prostate cancer have been followed according to the criteria of objective response of the National Prostatic Cancer Project (NPCP). All patients received combination therapy with the antiandrogen Flutamide and the LHRH agonist (D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (or surgical castration, 10 patients) as first treatment. Forty-nine patients (26.3%) achieved a complete response as best response while 56 (30.1%) and 69 (37.1%) patients had partial and stable responses, respectively, and only 12 patients (6.5%) did not respond to treatment. The median times required to achieve stable, partial and complete responses were 155, 183 and 401 days, respectively. The best response achieved has a major influence on the probability of continuing response and survival. While the 50% probability of continuing response is more than 3 years for the complete responders, it is reduced to 630 and 517 days for partial and stable responders, respectively. While the non-responders have a median life expectancy of 10.0 months, this value is increased to 30.3 and 37.8 months for the stable and partial responders, respectively. The best probability of survival is for the complete responders with a 95.9% probability of survival at 3 years. There is no significant correlation between the time required to achieve a best response (phase 1) and the duration of the response before progression occurs (phase 2) or the time between progression and death (phase 3) for any of the categories of responses. A longer period of time required to achieve a complete response is associated with a longer survival. When analysis is made, in an attempt to predict response, of the baseline characteristics of the patients before treatment, a low number of bone metastases and better performance status are associated with a greater chance of achieving a complete response while partial, stable and progression responses cannot be predicted from the baseline characteristics. The present data show the importance of standardization of the objective criteria of response to treatment in advanced prostate cancer. Thus, the patients who achieve a complete response have a much more favorable prognosis while partial and stable categories of response have a closely similar prognosis which is inferior to the complete responders. Moreover, the present data indicate that the stable category of response has an important prognostic value which is almost superimposable and not statistically different from the partial response in terms of duration of response and survival.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Important prognostic value of standardized objective criteria of response in stage D2 prostatic carcinoma. 276 14

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

In addition to other known markers of the human prostate, it was shown that the prostatic fraction of the split ejaculate was rich in a 16-kDa protein with properties not described previously. This protein was purified from human seminal plasma using ammonium sulfate precipitation, DEAE-Sepharose CL-6B ion exchange chromatography, and gel filtration on Sephadex G-100. The purified protein showed a single prominent spot on two-dimensional gel electrophoresis. The sequence of the first 40 amino acids that could be positively identified was identical to that of a prostatic secretory protein of 94 amino acids (PSP94) previously designated as beta-inhibin. Antibodies produced in rabbits against the purified protein were used to develop a radioimmunoassay. These antibodies appeared to recognize only the NH2-terminal portion of the native molecule since they did not react with a synthetic peptide composed of the 28 C-terminal residues. The radioimmunoassay showed that the concentration of the protein was 1320 +/- 183 micrograms/ml in the seminal plasma of adult fertile men and 1134 +/- 136 micrograms/ml in vasectomized patients. In hypertrophic and adenocarcinomatous prostates, the concentrations were 326 +/- 156 and 104 +/- 23 micrograms/ml, respectively, while values were lower than 0.060 micrograms/ml in the testis, epididymis, vas deferens and liver. The blood plasma concentration was 0.019 +/- microgram/ml in 23 asymptomatic men 45 to 65 years old and 0.115 +/- 0.036 microgram/ml in eight patients with prostate cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation from human seminal plasma of an abundant 16-kDa protein originating from the prostate, its identification with a 94-residue peptide originally described as beta-inhibin. 361 Aug 13

Twenty-two patients with prostatic cancer were treated for 12 to 52 weeks with the luteinizing hormone-releasing hormone agonist, (D-Leu6)-des Gly-NH2 10-LHRH ethylamide (leuprolide). The clinical efficacy of leuprolide was evaluated at 12 weeks according to NPCP criteria. All seven patients with Stage B and C disease demonstrated a partial objective regression. The objective response rate in 12 previously untreated Stage D patients was 92% (partial regression: 5; stable disease: 6). In three relapsing Stage D patients, one demonstrated stable disease and two failed to respond to leuprolide therapy. Even though the dose of leuprolide used in this study was high, no serious side effects were observed in any patients. There was a large increase in serum FSH and LH levels during the first few days of treatment, but serum FSH and LH levels fell below the initial levels by 1 and 2 weeks, respectively. Serum testosterone fell to less than 1 ng/ml within 3 weeks, and at 12 weeks it was 7.99% of the initial level. The present study shows that chronic administration of leuprolide in high doses can safely and effectively reduce the level of serum testosterone in patients with prostatic cancer.
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PMID:Efficacy of (D-Leu6)-des Gly-NH2 10-LHRH ethylamide against prostatic cancer. 391 98

New approaches to the therapy for some endocrine-dependent tumors with analogs of hypothalamic hormones are being developed on the basis of experimental studies in animal models. Analogs of luteinizing hormone-releasing hormones (LH-RH) may open new vistas for the treatment of some hormone-dependent carcinomas. It has been clearly demonstrated that both agonistic and antagonistic analogs of LH-RH can inhibit the growth of rat prostate tumors. A successful treatment of androgen-dependent prostate cancer with agonistic analogs of D-Trp6-LH-RH, D-Ser(But)6des-Gly-NH2(10)-LH-RH ethylamide, and D-Leu6-des-Gly-NH2(10)-LH-RH ethylamide has been documented in several hundred patients. The data accumulated so far from clinical trials suggest that LH-RH agonists can be used as an effective endocrine therapy for prostate carcinoma, therapy avoiding the side effects of estrogen and the psychologic impact of castration. Experimental animal studies and some clinical trials suggest that LH-RH agonists and/or antagonists might also be useful in the treatment of breast cancer. The results of experiments with various hypothalamic analogs in animal models of chondrosarcomas, osteosarcomas, and other tumors appear to be encouraging, but the potential clinical efficacy of LH-RH analogs in the treatment of human hormone-sensitive cancers other than breast and prostate remains to be investigated. The approach to treatment of hormone-dependent tumors based on analogs of hypothalamic hormones might become a useful addition to conventional methods for cancer therapy.
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PMID:Potential use of analogs of luteinizing hormone-releasing hormones in the treatment of hormone-sensitive neoplasms. 636 68

Potent synthetic analogs of gonadotropin-releasing hormone produce parodoxical antireproductive effects when administered chronically. These compounds are minimally toxic and may exhibit no plateau of the dose-response curve even at very high doses. These considerations served as the basis for our systematic evaluation of [D-leucine6-desarginine-glycine-NH2(10)]gonadotropin-releasing hormone (GnRH-A) proethylamide in the very high dose range (i.e., 10-fold larger amounts than previously used). In rats given the analog for 12 wk, prostate, testis, and seminal vesicle weights were suppressed to a greater extent with 200 micrograms q.d. than with 40 micrograms q.d. (P less than 0.01 prostate, less than 0.01 testis, less than 0.01 seminal vesicles), indicating dose-response effects in the very high dose range. 200 micrograms of [D-Leu6-des-Gly-NH2(10]-GnRH-A consistently suppressed leutinizing hormone (LH) values at 6 and 12 wk (basal 71 +/- 9.5; 6 wk 34 +/- 3.8; 12 wk 28 +/- 5 ng/ml) whereas 40 micrograms suppressed LH variably (basal 33 +/- 3.8; 6 wk 17 +/- 3.9; 12 wk 32 +/- 5.2). Testosterone fell to 15 +/- 2.4 and 19 +/- 2.0 ng/100 ml in response to 200 micrograms q.d. and to 27 +/- 6.4 and 22 +/- 7.4 ng/100 ml with the 40-micrograms dose. These findings in the rodent prompted treatment of stage D prostate cancer patients with similarly high doses of [D-Leu6-des-Gly-NH2(10)]-GnRH-A. After treatment for 11 wk with 1,000 or 10,000 micrograms/d of the analog, testosterone and dihydrotestosterone levels transiently rose and then fell into the surgically castrate range (testosterone 19 +/- 4.4 ng/100 ml [D-Leu6-des-Gly-NH2(10)]-GnRH-A vs. surgically castrate 11 +/- 0.9 ng/100 ml, P = NS; dihydrotestosterone 15 +/- 1.7 ng/100 ml GnRH-A vs. surgically castrate 15 +/- 4.1 ng/100 ml. P = NS). However, unlike the chronic stimulatory effect on the pituitary at lower doses, very high dose therapy resulted in profound suppression of plasma and urine LH. Plasma levels fell to the limit of assay detectability, whereas the more sensitive urinary assay detected prepubertal levels of excretion (i.e., 64 +/- 8.4 mlU/h). The highly sensitive rat interstitial cell testosterone bioassay for LH also demonstrated a marked decline in LH to undetectable levels in 17/19 subjects. Clinical results with [D-Leu6-des-Gly-NH2(10)]-GnRH-A simulate those achieved by surgical castration in men with prostatic cancer as suggested by available preliminary data.
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PMID:Effect of very high dose D-leucine6-gonadotropin-releasing hormone proethylamide on the hypothalamic-pituitary testicular axis in patients with prostatic cancer. 640 25

Orchiectomy or chronic administration of the gonadotropin releasing hormone agonistic analogue D, Ser (TBU)6, des Gly-NH2(10) ethylamide (HOE 766) were employed as therapeutic maneuvers in 25 patients with advanced prostatic carcinoma. HOE 766 administration effectively suppressed plasma testosterone to castrate levels that persisted for as long as treatment continued. Surgical and medical castration resulted in a significant decrease in prostatic size; this became evident earlier for surgically than medically treated patients (P less than .05), but no difference existed after the third month of treatment. Symptoms and signs of prostatism improved in practically all the patients. Among patients with stage D2 disease, there was an improvement in five as far as bone radiological assessment was concerned. Alkaline phosphatase levels did not show appreciable changes in patients showing objective stable disease or partial response according to National Prostatic Cancer Project criteria. Radioimmunoassayable prostatic acid phosphatase levels became normal in two of two stage C, five of five stage D1, and eight of seventeen patients with stage D2 disease, a rise in prostatic acid phosphatase (PAP), in alkaline phosphatase, and deterioration in bone radiology were associated with clinical evidence of relapse; this occurred despite persistently low levels of plasma testosterone. Serum thyroxine, cortisol, and prolactin levels remained unchanged following orchiectomy or chronic administration of HOE 766. Practically all patients complained of hot flashes and experienced a decrease in libido and potency, but none developed gynecomastia or thromboembolic episodes. The data indicate that HOE 766 can be used safely as an alternative to castration or estrogens for the treatment of patients with androgen-dependent prostatic cancer.
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PMID:Gonadotropin-releasing hormone agonistic analogues in the treatment of advanced prostatic carcinoma. 641 29

We have used the paradoxical antigonadal effects of LHRH agonists as a chemical castration in advanced prostatic cancer. We report early results of a phase II study on the clinical efficacy of the LHRH agonist D-Ser (TBU)6, des-Gly-NH2(10) LHRH administered to patients with stage D prostatic carcinoma. Following dose-range finding studies using either intranasal (IN) (200 micrograms twice/day or 500 micrograms twice/day) or subcutaneous (SC) administration (50 micrograms once/day, we developed a sequential combination of SC (500 micrograms three times/day for seven days) and IN regimen that was administered for 3 to 16 months to a group of 23 patients with stage D prostatic carcinoma. Initiation of therapy was associated with a clinical flare in one patient during the first week of treatment. Mean serum testosterone levels were already decreasing at one week and remained inhibited to levels inferior to 1 ng/ml after the first four weeks of treatment. Overall assessment shows that within the first six months of treatment, 26% patients were improved, 39% were stabilized, and 35% were nonresponders. Fourteen patients were followed during the next six months: 29% continued to respond, 29% escaped, 21% remained stable, and 21% were nonresponders. Histologic studies from castrated patients showed changes in spermatogenesis correlating to the degree and duration of suppression of testicular steroidogenesis without signs of toxicity. Preliminary observations on the combination of the pure antiandrogen RU 23908 with Buserelin (n = 5) or castration (n = 3) suggest that the addition of an antiandrogen does not seem to improve the patients nonresponding to other hormonal suppressive therapy (Buserelin) administered before (n = 3) or concomitantly with the antiandrogen (n = 2). Three relapsing castrate patients responded to the antiandrogen, but the response was temporary in two (eight to nine months of therapy). No side effects other than hot flashes and decreased potency are related to LHRH agonist alone or to the low-dose antiandrogen. Multicenter trials will be necessary to delineate the place of LHRH agonist alone or LHRH agonist combined with an antiandrogen in the treatment of prostatic cancer.
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PMID:Preliminary results on the clinical efficacy and safety of androgen inhibition by an LHRH agonist alone or combined with an antiandrogen in the treatment of prostatic carcinoma. 641 32


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