Combined Treatment With LHRH Agonist and Pure Antiandrogen in Advanced Carcinoma of Prostate

Labrie, Fernand; Bélanger, Alain; Dupont, André; Emond, Jean; Lacoursiere, Y.; Monfette, G.

doi:10.1016/s0140-6736(84)91521-6

Cited by 44 publications

(6 citation statements)

References 7 publications

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“…There is a need for new agents to treat prostatic carcinoma (Williams and Bloom, 1984). An agent which reduces adrenal hormones as well as testosterone might have a greater therapeutic potential and maintain hormonal control for longer, as suggested by Labrie et al (1984). When given in higher and more frequent doses than in its usual role as an antifungal agent, ketoconazole has been found to block the synthesis of testosterone in both the testis and the adrenal (Pont et al, 1982 a and b).…”

mentioning

confidence: 99%

Ketoconazole as Primary Treatment of Prostatic Cancer

Moffat

Kirk²,

Tolley³

et al. 1988

British Journal of Urology

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Ketoconazole 400 mg 8-hourly was used as primary hormonal treatment in 12 patients with advanced prostatic carcinoma. Four patients were withdrawn because of side effects and 1 died. The 7 patients who tolerated the drug had a reduction in testosterone and adrenal androgens. Six patients were fully evaluable. There was one partial response with complete remission of symptoms. Two patients enjoyed a subjective response and 3 showed no response. Ketoconazole had an effective biochemical action but the side effects seen in this study severely limit its usefulness. Ketoconazole has now been withdrawn as a treatment for prostatic cancer. However, less toxic derivatives might prove a useful addition to the drugs available to treat this condition.

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confidence: 99%

Ketoconazole as Primary Treatment of Prostatic Cancer

Moffat

Kirk²,

Tolley³

et al. 1988

British Journal of Urology

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“…Although the experimental conditions and the compounds investigated were different, these results are at variance with our findings. Labrie et al claimed that simultaneous administration of the antiandrogens Anandron or flutamide is necessary to nullify the effect of [47-501. adrenal androgens, as well as to neutralize the influence of the transient rise in serum androgen which follows the initial treatment with agonistic analogs of LH-RH in men with prostate cancer [26,27,4446,64]. According to their rationale, when antiandrogen is part of the combination, it can compete with testosterone and interfere with testosterone transport into the prostate cell and/or with other processes and thus can neutralize the stimulatory effect of any remaining androgens on the growth of the tumor.…”

Section: Discussionmentioning

confidence: 99%

“…While these data in rats may not be extrapolated unequivocally to men with advanced prostate carcinoma, they nevertheless leave unanswered the question of whether the combination of LH-RH analogs with antiandrogens [44,45,64] is more effective in the latter species than LH-RH analogs alone, since the results of therapeutic approaches in rats with Dunning tumors usually correspond to what happens in men with prostate carcinoma [23]. The cost of antiandrogens, their potential toxicity [46], and inconvenience of daily usage [50] may be additional negative factors.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Combination of the Agonist D-Trp-6-LH-RH and the Antiandrogen Flutamide in the Treatment of Dunning R-3327H Prostate Cancer Model

Redding

1985

Journal of Urology

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The therapy for the treatment of prostate cancer and other sex-steroiddependent tumors based on agonists of LH-RH has been made more practical and efficacious by the development of a long-acting formulation of microcapsules of D-Trp-6-LH-RH for controlled release. Antiandrogens, which neutralize the effect of endogenous androgens, have been used also in the management of prostate cancer in man. The effects of a simultaneous administration of the antiandrogen flutamide and microcapsules of the agonist D-Trp-6-LH-RH were studied in the Dunning R-3327H rat prostate adenocarcinoma model to determine whether the combination of these two drugs might inhibit tumor growth more effectively than single agents. Microcapsules of D-T@-LH-RH, calculated to release a controlled dose of 25 pglday for a period of 30 days were injected intramuscularly once a month. Flutamide was administered SC at a daily dose of 25 mglkg. The therapy was started 100 days after the tumor transplantation and continued for 60 days. Tumor weights and volumes were significantly reduced in rats treated with microcapsules or flutamide alone, but the former drug inhibited tumor growth more than the latter. The combined treatment of flutamide and microcapsules significantly decreased tumor weight and volume, but did not exert a synergistic effect on tumor growth, the reduction being smaller for the combination than for the microcapsules alone. There was a significant elevation of serum testosterone, LH, and prolactin in rats treated with flutamide. On the other hand, in rats given microcapsules of D-Trp-6-LH-RH, testosterone fell to castration levels within 7 days and remained at nondetectable values, serum LH and prolactin levels being also suppressed in this group. The combined administration of microcapsules and flutamide also significantly decreased serum testosterone to nondetectable levels by day 7 and suppressed serum LH and prolactin. Our findings raise doubts of whether the daily administration of the combination of LH-RH agonist with an antiandrogen offers an advantage over the use of microcapsules of an agonist like D-Trp-6-LH-RH alone in the treatment of prostatic carcinoma.

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“…25 -53 - 60 In some clinical trials, a combination of HOE 766 with antiandrogens RU-23908 or flutamide was used for treatment of patients with stage C and D 2 prostate carcinoma. 34,35,61,62 It was stated that the combined treatment with the LHRH analog and antiandrogen is more effective than the analog alone. 61 On the basis of these results we decided to study the effects of a simultaneous administration of the antiandrogen flutamide and microcapsules of the agonist D-Trp 6 LHRH in the Dunning R3327H rat prostate adenocarcinoma model to determine whether the combination of these two drugs might inhibit tumor growth more effectively than single agents.…”

Section: Prostate Cancermentioning

confidence: 99%