[1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II): an endocrine-active platinum complex with a specific prostatic tumor-inhibiting activity

Abstract

[1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethlenediamine]dichloroplatinum(II), (I) a Pt complex with endocrine activity and a specific effect on hormone-dependent mammary tumors, was tested for its tumor-inhibitory activity in the hormone-sensitive R 3327 and Nb prostate carcinoma models of the rat and for its endocrine activities in comparison to the ligand L (the non-Pt part of the drug) and diethylstilbestrol (DES). Established tumors of the R 3327 prostate tumor were strongly inhibited by I. Its effect equaled that of DES and was better than that of L. Accessory sex organ wts. and testosterone levels were strongly reduced by I as well as L. This antigonadotrophic effect, which is almost comparable to DES, was confirmed in 10-day expts. with intact, mature mice and rats, whereas a direct antiandrogenic activity was not given. A part of the antitumor action of I is therefore due to this antigonadtrophic activity. Affinities to estrogen, progesterone, and androgen receptors, however, were very low. The hormone-sensitive Noble Nb-R prostatic carcinoma was almost completely inhibited by I, whereas L had only a weak effect. As I has no effect on the hormone-independent R 3327 HI prostate tumor and as its effect on hormone-dependent tumors is better than that of the ligand L in spite of their similar endocrine properties, an apparently specific antiproliferatives effect of I only on hormone-dependent prostate tumors is obvious. This was further shown in a long-term expt. with the R 3327 prostate carcinoma. Whereas tumors in the castration group relapse from androgen ablation and exerted a progressive tumor growth, therapy with I almost completely prevented this relapse phenomenon. After 25 wk of treatment, I inhibited tumor growth by 90% compared to castration. Thus, I, with an apparently specific effect on hormone-dependent prostate tumors, can be of value for the therapy of the prostatic carcinoma.