[1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloro-platinum (II), (C), a platinum 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 and diethylstilbestrol (DES). Established tumors of the R 3327 prostate tumor were strongly inhibited by C. Its effect equaled that of DES and was significantly better than that of L. Accessory sex organ weights and testosterone levels were strongly reduced by C as well as L. This antigonadotrophic effect, which is almost comparable to DES, was confirmed in 10 day experiments with intact, mature mice and rats, whereas a direct antiandrogenic activity was not given. A part of the antitumor action of C is therefore due to this antigonadotrophic 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 C, whereas L had only a weak effect. As C has no significant effect on the hormone-independent R 3327 HI prostate tumor and as its effect on hormone-dependent tumors is significantly better than that of the ligand L in spite of their similar endocrine properties, an apparently specific antiproliferative effect of C only on hormone-dependent prostate tumors is obvious. This was further shown in a long-term experiment with the R 3327 prostate carcinoma. Whereas tumors in the castration group relapsed from androgen ablation and exerted a progressive tumor growth, therapy with C almost completely prevented this relapse phenomenon. After 25 weeks of treatment, C inhibited tumor growth by 90% compared to castration. Owing to these results, this new endocrine active platinum complex with an apparently specific effect on hormone-dependent prostate tumors can be of value for the therapy of the prostatic carcinoma.
The anti-oestrogen zindoxifene was originally developed as a drug for the treatment of hormone-dependent mammary carcinomas. Experiments with rats bearing androgen-dependent prostatic tumours revealed anti-neoplastic activity of zindoxifene on these tumours also. Therefore, the inhibitory effect of this drug was studied in various prostatic tumour models in comparison to the anti-oestrogen tamoxifen and to castration. The growth of the hormone-dependent Dunning R3327 H tumour was strongly inhibited by zindoxifene (4 mg/kg), which was more effective than tamoxifen (43% T/C vs 87% T/C, the ratios of tumour weights in control and drug-treated rats). Zindoxifene was able to delay the relapse of these tumours by 7 weeks in comparison to castration. The experiments with Noble Nb-R prostatic tumours showed that administration of zindoxifene (5 mg) is superior to castration (5% T/C vs 52% T/C). The growth of tumours in castrated rats was completely inhibited by administration of zindoxifene. Therefore a peripheral mode of action has to be assumed.
For the development of new nonsteroidal antiandrogens a series of 4-nitro-3-trifluoromethyldiphenylamines was synthesized and compounds were tested for their affinities to steroid hormone receptors and for antiandrogenic activities. These compounds were synthesized by reacting 4-nitro-3-trifluoromethylphenylsulfocyanamide-sodium (4) with the corresponding aromatic amines to give the N-(4-nitro-3-trifluoromethylphenylsulfonyl)-N'-phenylguanidines . The crude products were then converted to the desired diphenylamines by Smiles rearrangement and hydrolysis. 2-Hydroxy-4'-nitro-3'-trifluoromethyldiphenylamine (13), which shows a relative binding affinity (RBA) to the androgen receptor (AR) of 6.5% of that of testosterone, exerts a higher affinity than hydroxyflutamide (RBA = 4.5). Shift of the hydroxy-function to position 3 or 4 as well as N-methylation caused a decrease in AR-affinity. Compounds exerting AR-affinity were tested for antiandrogenic activity. Compound 13 showed the best antiandrogenic effect, though less than the well-known antiandrogen flutamide.
For many years, diethylstilbestrol (DES) and its diphosphate (DESPP; Honvan) have been standard therapies for prostatic carcinoma. The effects of DES, its monophosphate (DESP) and of DESPP on the weights of accessory sex organs of mice and rats, and on the experimental Noble Nb-H and Nb-R prostatic carcinomas of the rat were, therefore, compared. In intact mature mice, all three compounds led to a strong and dose-dependent inhibition of seminal vesicle weights and testosterone levels, whereas only a slight antiandrogenic activity in castrated mice was found. In intact rats, DES, DESP and DESPP strongly inhibited accessory sex organ weights and testosterone levels. In castrated rats, however, no antiandrogenic activity was determinable. The prostate carcinoma-inhibiting effects of DES and DESPP were tested in comparison with castration in the transplantable hormone-sensitive Nb-H and Nb-R prostatic carcinoma in rats. Whereas castration caused only a retardation of tumor growth, DES and DESPP (3 x 0.1 mg/kg and 1.0 mg/kg weekly s.c.) led to an almost complete inhibition, which was significantly (P less than 0.01) better than the effect of castration. As the weights of accessory sex organs were identically reduced by either castration or the estrogens, a direct tumor-inhibiting effect of DES and DESPP in addition to their testosterone-lowering activity is obvious. This was proved in an experiment with castrated rats. The only slightly inhibitory activity of castration was strongly potentiated by concomitant administration of DES. Moreover, histological examinations revealed that Nb-H and Nb-R tumors were much more damaged by treatment with DES or DESPP than after castration. Morphometry of the tumors showed that tumor reduction is associated with a decrease in the ratio of the epithelial to the stromal density, i.e. there was an even more pronounced decrease in epithelial cells than that found by merely measuring tumor area. These studies show that the prostate carcinoma-inhibiting effect of DES and DESPP in the Nb model is superior to the effect of castration and that they act directly on the tumor cells used, even in castrated rats.
Zur Entwicklung potentieller nichtsteroidaler Antiandrogene wurden N‐(4‐Nitro‐3‐trifluormethylphenyl)‐cyclohexanoylamide und ‐benzamide, sowie N‐(3,4‐Dichlorphenyl)‐ und N‐(3,4,5‐Trichlorphenyl)‐benzamide synthetisiert. Die Hydroxycyclohexylverbindung 3 zeigte eine deutlich höhere Affinität zum Androgenrezeptor (AR) als Hydroxyflutamid. Der Ersatz des Hydroxycyclohexylringes durch einen Hydroxyphenylring führte zu einem starken Abfall der AR‐Affinität. Verbindungen mit AR‐Affinität wurden auf antiandrogene und androgene Wirkung geprüft.
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