Molecular chemotherapy and chemotherapy : A new front against late-stage hormone-refractory prostate cancer

摘要

*This article is free to read on the publisher's website*\ud\udPurpose: Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase–mediated, gene-directed enzyme-prodrug therapy (PNP-GDEPT) with docetaxel against CRPC has superior efficacy in comparison with individual treatments.\ud\udMethods: The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment.\ud\udResults: The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the individual modalities, a combination of the 2 led to a marked reduction in “local and distant” tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T-helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy.\ud\udConclusion: PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings; these outcomes have implications of translational potential for improved treatment and management of CRPC patients. Clin Cancer Res; 17(12); 4006–18. ©2011 AACR.\ud\ud\udTranslational Relevance\ud\udRecent activity of docetaxel-based chemotherapy against clinically incurable castration-resistant prostate cancer (CRPC) has raised hopes of finding a tangible treatment option against this insidious disease. Inadequacy of single-agent treatments coupled with increasing detection of PC in younger men necessitates the development of novel combination regimens that are clinically feasible and can further improve the outcomes. Particularly designed on this premise, this study unequivocally shows the success of combining purine nucleoside phosphorylase–directed enzyme prodrug therapy (PNP-GDEPT) with conventional docetaxel against CRPC in xenogeneic and syngeneic orthotopic mouse models, including pseudometastases. This combination has potential for quick translation to the clinical setting (i) because all components are clinically relevant, including the prodrug fludarabine phosphate, which engenders PNP-GDEPT–mediated cytotoxicity, and (ii) because of potential for enhanced efficacy against local/metastatic CRPC at lower individual therapeutic doses with no additional toxicities. Finally, a clear correlation noted between the tumor burden and serum Th2-cytokine levels indicates the potential for noninvasive monitoring of treatment outcomes in the clinical setting.