The effect of a combination of zindoxifene and cisplatin on Dunning R3327-G prostatic carcinomas of the rat

Abstract

Endocrine therapy of hormone-dependent prostatic carcinomas can be very effective at the beginning. However, tumour growth eventually resumes possibly because of the presence of androgen-independent cell clones. Addition of a cytotoxic agent to the hormonally active drug at an early stage could possibly delay progression of disease. Therefore, we studied the effects of hormonal and cytostatic treatment in a rat prostate carcinoma model: freshly transplanted Dunning R3327-G prostatic tumours of the rat were treated with the partial antioestrogen zindoxifene and cisplatin alone and in combination. In addition we tested a 2-phenylindole-linked platinum complex 3-PtCl2, which contains both effective functions. This particular complex had only a weak non-significant inhibitory effect on tumour growth. Comparing monotherapies with zindoxifene or cisplatin at various dose levels with the corresponding combinations, it became evident that the latter treatment was significantly more effective than the use of single agents. A very low dose of 0.4 mg cisplatin together with 2 mg/kg zindoxifene inhibited tumours by 91%, which was close to the effects of castration or diethylstilbestrol (1 mg). The analyses of accessory sex organs revealed much weaker oestrogenic side-effects than those observed with diethylstilbestrol at an equivalent dose. These results demonstrated that it is possible to increase the efficacy of hormonal therapy of prostatic carcinomas by concomitant administration of cisplatin and reduce side-effects of oestrogenic drugs.