Molecular Chemotherapy and Chemotherapy: A New Front against Late-Stage Hormone-Refractory Prostate Cancer

• Published in: Clinical cancer research 2011-06, Vol.17 (12), p.4006-4018
• Main Authors: PAL SINGH, Preetiner, JOSHI, Swapna, RUSSELL, Pamela J, VERMA, Nirupama D, XIAOCHUN WANG, KHATRI, Aparajita
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Biological and medical sciences; Cell Line, Tumor; Cytokines - blood; Dose-Response Relationship, Drug; Drug Synergism; Genetic Vectors - genetics; Gynecology. Andrology. Obstetrics; Humans; Lung Neoplasms - enzymology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Male; Male genital diseases; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasm Staging; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - mortality; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Purine-Nucleoside Phosphorylase - genetics; Purine-Nucleoside Phosphorylase - metabolism; Taxoids - pharmacology; Th2 Cells - immunology; Tumor Burden - drug effects; Tumor Burden - genetics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-0248

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. 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. 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. 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.