Castration is a prerequisite for the inhibitory effect of metronomic chemotherapy on the growth of experimental castration-resistant prostate cancer

Abstract

Background: Low-dose metronomic chemotherapy (LDMC) is an alternative for treatment of patients with late-stage prostate cancer (PC) not susceptible to regular chemotherapy due to its severe side effects. The exact working mechanisms of LDMC have not been established, although anti-angiogenic effects have been identified. In PC, several studies show clinical effects from LDMC but the mode of action and the role of androgen signaling for its effect are not known. In this study, we used a xenograft model to evaluate the effect of LDMC on PC growth in relation to androgen deprivation.Material and methods: Subcutaneous human castration-resistant PC xenografts were treated with LDMC using cyclophosphamide (CPA). Treatment effect was compared to treatment with maximum tolerated dose (MTD) and also between intact and castrated mice. Microvessel density (MVD), and factors important for angiogenesis were analyzed with immunohistochemistry and real-time-PCR.Results: Tumors treated with LDMC were 50% smaller than untreated controls. Tumors in non-castrated mice were not affected by LDMC, but in an androgen receptor (AR) negative tumor model, tumor inhibiting effect were seen in both intact and castrated animals, indicating mechanism via AR. MTD resulted in similar growth inhibition as LDMC in castrated mice, but resulted in severe weight loss. Despite that LDMC induced TSP1 mRNA expression, and the hypoxic area in the tumors was slightly increased, no decrease in MVD was detected.Conclusions: This study shows that a low-dose metronomic scheduling of CPA was as efficient as MTD treatment, and resulted in fewer side effects. It also demonstrates that a functional androgen signaling axis inhibits this effect despite the castration-resistance of the tumor cells. The anti-angiogenic nature of the effect of LDMC could not be confirmed and further studies to elucidate the working mechanism for treatment response are needed.