Effect of zindoxifene on experimental prostatic tumours of the rat

Abstract

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.

Platinum(II) complexes interfering with testicular steroid biosynthesis: drugs for the therapy of advanced or recurrent prostate cancers? Preclinical studies

“…Antiestrogens could have an anti-prostate cancer activity, e.g., tamoxifen (Schneider et al 1991;Ryan and Small 2003) and zindoxifene (Schneider et al 1991;. We could show that the shift of the two OH groups in DES into the meta-positions led to a compound with antiestrogenic potency (Kranzfelder et al 1980).…”

“…A survey of Dunning PC models is given by Tennant et al (2000). The used AR + Dunning R3327-H PC is inhibited by cDDP, orchiectomy and other endocrine therapeutic measures like administration of the non-steroidal estrogen DES and the ''partial'' antiestrogen zindoxifene (Schneider et al 1991), but differs from the subtype G (used in the test of meso-1-PtSO 4 ) by a slower tumor cell proliferation rate.…”

“…A randomized prospective clinical study on a combination of castration plus cisplatin (cDDP) showed that after 6 weeks the number of patients with progressing tumors was much smaller in the group receiving both treatments than in the group with castration alone (Burk and Jonas 1987). Preclinical experiments of von Angerer et al (1992) revealed that the activity of the ''partial'' antiestrogen zindoxifene on the AR + Dunning R3327-G PC of the rat-presumably caused by reduction of the testosterone level to castration values due to its residual estrogenic potency-could also be enhanced by simultaneous administration of cDDP (to the mode of action of zindoxifene compare Schneider et al 1987Schneider et al , 1991.…”

Optimization of cisplatin for the treatment of hormone dependent tumoral diseases

“…It is remarkable that zindoxifene was even able to delay the relapse of the Dunning R 3327-H PC by 7 weeks in comparison to castration [29]. Tamoxifen produced only marginal inhibitory effects on this tumor [29].…”

“…A randomized, prospective clinical study on a combination of castration (causing androgen ablation) and cDDP showed that after 6 weeks the number of patients with progressing tumors was much smaller in the group receiving both treatments than in the group with castration alone [26]. Pre-clinical experiments of von Angerer et al [27] revealed that the activity of the "partial" antiestrogen zindoxifene on the androgen receptor-positive (AR + ) Dunning R3327-G PC of the rat -presumably caused by reduction of the androgen level to castration values due to its residual estrogenic potency -could also be enhanced by simultaneous administration of cDDP (to the mode of action of zindoxifene compare Schneider et al [28,29]). …”