Faculty of Medicine, Oncology Research Centre, University of New South Wales, Australia.
Prince of Wales Hospital, Clinical Science Building, level 2, Prince of Wales Hospital, High Street, Randwick, Sydney, New South Wales, 2031, Australia.
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 if 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 the individual treatments.
The invitro 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, an evaluation of serum-cytokine and -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 to the individual modalities, combination of the two led to a marked reduction in "local and distant" tumor growth in vivo, importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune-cell infiltration and altered serum cytokine levels. Further, a lowering of Th2 cytokines, MCP1, 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 in immunodeficient settings; the outcomes have translational potential for improved treatment and management of CRPC patients.
Written by:
Singh PP, Joshi S, Russell PJ, Verma ND, Wang X, Khatri A. Are you the author?
Reference: Clin Cancer Res. 2011 Apr 29. Epub ahead of print.
doi: 10.1158/1078-0432.CCR-11-0248
PubMed Abstract
PMID: 21531822
UroToday.com Prostate Cancer Section
