RRC ID 4751
Author Khatri A, Husaini Y, Ow K, Chapman J, Russell PJ.
Title Cytosine deaminase-uracil phosphoribosyltransferase and interleukin (IL)-12 and IL-18: a multimodal anticancer interface marked by specific modulation in serum cytokines.
Journal Clin Cancer Res
Abstract PURPOSE:To test the effects of a new combination, cytosine deaminase (CD) + uracil phosphoribosyltransferase (UPRT)-mediated gene-directed enzyme prodrug therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine prostate and remote tumor deposits, (b) mouse survival, and (c) T helper (Th) 1/Th2 serum cytokine balance with a special focus to assess correlation with tumor burden/survival.
EXPERIMENTAL DESIGN:Efficacy of intraprostatic administration of adenovirally delivered murine IL-12 and IL-18 against orthotopic RM1 tumors and lung pseudometastases was assessed in C57BL/6 mice. At necropsy, tumor growth, lung colony counts, effects on immune cell infiltration, vasculature, apoptosis, and proliferation were estimated. Next, CDUPRT-GDEPT + cytokines were tested at suboptimal doses in mice with RM1CDUPRT prostate tumors/RM1 lung deposits and analyzed as above. Effects on mouse survival were also assessed. Host immune responses to different treatments were assessed by monitoring 11 serum cytokines using Luminex technology.
RESULTS:Our data show that IL-12 and IL-18, when combined with CDUPRT-GDEPT, caused significant reduction in local RM1 tumors and lung colonies with enhanced long-term survival versus individual treatments. A dramatic enhancement of tumor infiltration by a wider repertoire of immune cells and disruption of vasculature implied the combination to be more immunostimulatory and antiangiogenic. Remarkably, lowering of serum IL-4 and monocyte chemoattractant protein-1 (MCP-1) was consistently associated with lower tumor burden (local and systemic), and this, rather than an increase in Th1 cytokines, better predicted treatment efficacy. In addition, mouse survival correlated with substantially higher cytokine (Th1/Th2) levels after treatment.
CONCLUSION:Locoregional application of CDUPRT-GDEPT and IL-12/IL-18 was effective against local and systemic prostate cancer and improved survival. Monitoring serum levels of IL-4 and MCP-1 may accurately reflect tumor burden and, hence, host response to therapy.
Volume 15(7)
Pages 2323-34
Published 2009-4-1
DOI 10.1158/1078-0432.CCR-08-2039
PII 1078-0432.CCR-08-2039
PMID 19318483
MeSH Animals Apoptosis Cell Line, Tumor Cell Proliferation Combined Modality Therapy Cytokines / blood* Cytosine Deaminase / genetics* Flucytosine / therapeutic use Interleukin-12 / genetics* Interleukin-18 / genetics* Lung Neoplasms / secondary Lymphocytes, Tumor-Infiltrating / immunology Male Mice Mice, Inbred C57BL Pentosyltransferases / genetics* Prodrugs / therapeutic use Prostatic Neoplasms / immunology Prostatic Neoplasms / pathology Prostatic Neoplasms / therapy* Survival Analysis Th2 Cells / immunology
IF 10.107
Times Cited 12
DNA material Ax1 CI-mIGIF (RDB01735)