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

Abstract

[Meso-1,2-bis(2,6-dihalo-3/4-hydroxyphenyl)ethylenediamine]platinum(II) complexes (meso-1-PtLL': 2,6-F(2),3-OH; meso-2-PtLL': 2,6-F(2),4-OH; meso-3-PtLL': 2,6-Cl(2),3-OH; meso-4-PtLL': 2,6-Cl(2),4-OH; L = OH(2), L' = OSO(3) or L,L' = Cl(2)) were designed with the aim to get drugs comprising both cytotoxic and testosterone level lowering potencies. It is assumed that such compounds are more efficient than the established endocrine therapeutic measures and can affect the development of hormone refractory prostate cancer (PC). With exception of meso-3-PtLL' all Pt-complexes and the comparison compound cisplatin significantly reduced the testosterone level in experiments on male rats. However, in the test on the Dunning R3327 PC of the rat only cisplatin and meso-4-PtLL' showed a significant anti-tumor activity at well-tolerated dose ranges. Meso-4-PtLL' also significantly extended the time to disease progression in comparison with orchiectomy in this tumor model. Interestingly, the relapsed tumor, too, responded to meso-4-PtLL' as demonstrated in a long-term study on orchiectomized rats bearing Dunning R3327 PC grafts. This effect cannot be ascribed to cytotoxic effects of meso-4-PtLL' because of its inactivity on the human LNCaP/FGC PC cell line. Therefore, the contribution of an additional mechanism to the anti-prostate cancer activity of meso-4-PtLL', presumably owing to its estrogenic potency, must be considered. This assumption was supported by test results with diethylstilbestrol (DES) (non-steroidal estrogen) on the Dunning R3327 PC of the rat relapsed after orchiectomy. This tumor model was strongly inhibited by DES. The possible mode of action of meso-4-PtLL' is thoroughly discussed.

Optimization of cisplatin for the treatment of hormone dependent tumoral diseases

“…The harmful effect of DES on AR − PC cells was also demonstrated in a long-term experiment on the Dunning R3327-H PC of the rat, in which the duration of the inhibitory effect until disease progression was significantly extended in comparison to orchiectomy [90]. The marked inhibitory effect of DES on the AR − PC was also seen in rats bearing implants of the Dunning R3327-H PC relapsed after castration [90]. This tumor model was resistant against androgen ablation indicating an androgen receptor negative status.…”

“…The studies suggest that in addition to the moderate cytotoxic potency, evident from cell culture experiments with DES [90], ER ␤ -mediated processes like modulation of immune response [97], triggering of anti-angiogenesis [98], reduced proliferation and increased differentiation of tumor cells [54] are also responsible for the growth inhibition of AR − PC after DES administration. The DES effect cannot arise from a simple direct interaction of the drug with the tumor cells (e.g.…”

“…It is noteworthy that in contrast to E 2 the non-steroidal estrogen DES, which was introduced into prostate cancer therapy by Huggins and Hodges as early as 1941 [89], causes moderate, but significant cytotoxic effects on prostate cancer cells [90]. Therefore, DES is more suitable as carrier ligand in anti-prostate cancer active Pt-complexes than E 2 .…”

“…DES is used in the therapy of advanced prostate cancer after failure of surgical or medical castration to control the manifestation of the disease [92][93][94][95][96]. The harmful effect of DES on AR − PC cells was also demonstrated in a long-term experiment on the Dunning R3327-H PC of the rat, in which the duration of the inhibitory effect until disease progression was significantly extended in comparison to orchiectomy [90]. The marked inhibitory effect of DES on the AR − PC was also seen in rats bearing implants of the Dunning R3327-H PC relapsed after castration [90].…”

“…The DES effect cannot arise from a simple direct interaction of the drug with the tumor cells (e.g. by interfering with processes of the DNA replication), since marked proliferation-inhibiting effects of DES on the human LNCaP/FGC PC cell line were only determined at a concentration about three times higher than that causing maximal tumor inhibition in animal experiments [90].…”