Treatment of advanced prostatic carcinoma with D-Trp-6-LH-RH

Bárcena, David González; Pérez, Pilar; Ureta, S.; Berea, Hector; Graef, Alicia; Becerril, Mayra; Comaru‐Schally, Ana Maria; Schally, A. V.

doi:10.1016/0022-4731(84)90472-2

Cited by 4 publications

(5 citation statements)

References 16 publications

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“…The effects on the levels of androgen receptors and on competitive binding to androgen receptors are unknown. Nevertheless, we have seen, as have Gonzalez-Barcena et a1 [38], some objective effects of D-Trp-6-LH-RH in castrated patients. This suggests that some human prostatic cancer cells possess, as do rat Dunning carcinoma cells, LH-RH binding sites [21].…”

Section: Discussionsupporting

confidence: 55%

Phase II trial with D‐Trp‐6‐LH‐RH in prostatic carcinoma: Comparison with other hormonal agents

Mathé¹,

Schwarzenberg²,

VoVan³

et al. 1986

The Prostate

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Various approaches to hormonal treatment of prostate carcinoma are discussed. Eighty-one patients with prostatic carcinoma, eight with stage B, nine with stage C, and 64 with stage D disease, were treated subcutaneously daily for 3 months with the LH-RH agonist D-Trp-6-LH-RH (Decapeptyl) in order to evaluate the incidence of remissions according to WHO recommendations for oncologic trials. The findings were compared to those obtained with other hormonal therapies of prostatic carcinoma according to the statistical method of "expected response rate" as adapted by Lee and Wesley for phase II trials. Treatment with D-Trp-6-LH-RH greatly reduced serum LH and testosterone levels without raising serum prolactin. After 1-2 weeks of therapy, there was relief of subjective symptoms and a reversal of the signs of prostatism as well as a marked decrease in bone pain. At 90 days 52 patients had complete relief of prostatism and 21 had only mild signs and symptoms. Seventy patients were experiencing no bone pain and an additional six had only mild pain. Prostatic size, evaluated by rectal examination and transabdominal ultrasonography, reverted to normal in 26.4% of patients (complete remission) and was reduced by more than 50% in an additional 17.6% (partial remission), the overall rate of complete plus partial regression of prostatic enlargement being 44%. Scans showed a major improvement of bone lesions in 14.8% of cases. This response increased to 37% after more than 6 months of follow-up. Prostatic acid phosphatase levels were decreased by more than 50% in 61% of the patients, but this test appears to be a less valid marker than the lipid-associated sialic acid (LASA). The increase in LASA before treatment and a reduction after treatment can frequently be correlated with the objective volume of the neoplasms. No flare-up of the disease was encountered, and there were no side effects except for impotence. Statistical analyses of results by the method of Lee and Wesley indicated that the incidence of complete and partial regression (CR and PR) observed with D-Trp-6-LH-RH was not significantly different from that recorded in previous studies for another LH-RH analog, Buserelin. However, CR and PR obtained with D-Trp-6-LH-RH (44%) were significantly higher than with subcapsular orchiectomy (22%). Hormonal effects and some other actions of D-Trp-6-LH-RH were compared and contrasted with those produced by castration, estrogens, antiandrogens, and progestogens.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussionsupporting

confidence: 55%

Phase II trial with D‐Trp‐6‐LH‐RH in prostatic carcinoma: Comparison with other hormonal agents

Mathé¹,

Schwarzenberg²,

VoVan³

et al. 1986

The Prostate

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“…Prolonged treatment is necessary in these conditions in order to achieve the desired suppression. In this study and in our previous trial [5] in patients with prostatic carcinoma, 100 pg D-Trp-6-LH-RH/day proved to be an effective therapeutic dose and persistent blockade of the pituitary-testicular axis was obtained as long as the analog was administered.…”

Section: Discussionsupporting

confidence: 59%

“…The results of Roger et a1 [ 181 and Parmar et al [ 191 in men with prostate cancer attest to the high clinical efficacy of once a month administration of microcapsules of suppressing testosterone secretion. The accumulated results [1][2][3][4][5][6][7]18,19] reinforce the view that long-term therapy with agonists of LH-RH is a viable alternative to surgical castration or therapy with estrogens in men with metastatic prostate cancer.…”

Section: Discussionmentioning

confidence: 80%

“…Our previous reports showed that the initial administration of high doses of D-Trp-6-LH-RH causes a marked elevation of plasma LH and FSH that lasts more than 24 hours. However, 1 to 3 weeks after starting the therapy, LH, FSH, and testosterone levels fall and remain in the subnormal range as long as the treatment is continued [ 5 ] . Kerle et al [8] reported recently that in some patients with prostate cancer, treatment with ICI analog 118630 failed to suppress LH and testosterone levels 6-12 months after initiation of this therapy.…”

Section: Introduction Prostate Cancermentioning

confidence: 99%

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Persistent blockade of the pituitary‐gonadal axis in patients with prostatic carcinoma during chronic administration of D‐Trp‐6‐LH‐RH

et al. 1986

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Forty patients with stage D2 prostatic carcinoma were treated for up to 30 months with D-Trp-6-LH-RH. The analog was given s.c. once daily at a dose of 1 mg/day for the first 7 days. Subsequently, the dose was reduced to 100 micrograms/day. In follow-up studies, 30 men continued this therapy for up to 24 months. Blood samples were taken before the injection of the analog and 1, 2, 4, and 6 hours later. Serum LH, FSH, and testosterone levels were measured by RIA every month for 2 years. The initial administration of 1 mg D-Trp-6-LH-RH caused a marked elevation of LH and FSH, which lasted more than 24 hours. However, 1 month later and throughout the therapy, the basal values of LH and FSH were below the normal range and no increase in serum gonadotropins levels was obtained after administration of the analog. Initial plasma testosterone was within normal limits, but during treatment with D-Trp-6-LH-RH it fell to castration levels, and no increases were seen during the 6 hours following the injection of the analog. These results show that chronic administration of D-Trp-6-LH-RH, at the doses used, blocks the pituitary-gonadal axis and that the escape phenomenon from the effects of the LH-RH agonists-induced blockade does not occur under our conditions in contrast to observations of Kerle et al with the I.C.I. Analog 118630 (8). The accumulated results reinforce the view that long-term therapy with agonists of LH-RH is the preferred alternative to surgical castration or therapy with estrogens in men with metastatic prostate cancer.

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“…It is well established that hormonal therapy can inhibit the growth of prostate cancers in experimental models and in patients [1][2][3][4][5][6][7][8][9][10][11][12][13]. Tissues of the male accessory sex glands need testosterone for normal development, and hormone-dependent prostatic tumors also require androgens for growth.…”

Section: Introductionmentioning

confidence: 99%

Histological changes in dunning prostate tumors and testes of rats treated with LH‐RH antagonist SB‐75

et al. 1991

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Rats bearing Dunning R-3327 hormone-dependent prostate tumors were treated with LH-RH antagonist SB-75 in the form of microcapsules for sustained delivery administered every 3 weeks and which released 24, 48, 72 micrograms/day respectively. The effects were compared with those of microcapsules of the agonist D-Trp-6-LH-RH releasing 25 micrograms/day. Both types of LH-RH analogs significantly inhibited tumor growth over a period of treatment lasting 8 weeks. The effect of SB-75 was dose-dependent. The total inhibition of spermatogenesis, as well as atrophic signs in the prostate and seminal vesicles, demonstrated a marked suppression of the pituitary-gonadal system by these analogs. The histological signs of tumor regression were analyzed. The vascular content of tumors did not change after the treatments, but an increased amount of connective tissue was found in the treated tumors, especially after administration of SB-75. Both the agonist and the antagonist caused a moderate decrease of the number of mitotic cells and a marked increase of apoptosis in the tumors. The apoptotic index, i.e. the percentage of tumorous glands showing signs of apoptosis, reached 40-50% in treated groups, compared to only 15% in controls. An apoptotic index of 60% was noted in a separate group of rats treated with 200 micrograms SB-75/animal/day for 3 days. The signs of enhanced apoptosis disappeared 1 week after the short-term treatment. The induction of apoptosis by LH-RH analogs seemed to be of greater importance in tumor growth inhibition than their antimitotic effect. These results extend our previous observations on the efficacy of LH-RH antagonists in inhibition of various cancers. This histopathologic evaluation clearly supports our contention that modern antagonists of LH-RH, free of edematogenic effects, inhibit the growth of Dunning prostate tumors. Because of the immediate inhibitory effects, the use of LH-RH antagonists might lead to an improvement in the clinical response in patients with prostate cancer.

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Treatment of advanced prostatic carcinoma with D-Trp-6-LH-RH

Cited by 4 publications

References 16 publications

Phase II trial with D‐Trp‐6‐LH‐RH in prostatic carcinoma: Comparison with other hormonal agents

Phase II trial with D‐Trp‐6‐LH‐RH in prostatic carcinoma: Comparison with other hormonal agents

Persistent blockade of the pituitary‐gonadal axis in patients with prostatic carcinoma during chronic administration of D‐Trp‐6‐LH‐RH

Histological changes in dunning prostate tumors and testes of rats treated with LH‐RH antagonist SB‐75

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