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Thermal Sensitization Using Induced Oxidative Stress Decreases Tumor Growth in an In Vivo Model of Hyperthermic Intraperitoneal PerfusionGrowth in an In Vivo Model of Hyperthermic Intraperitoneal Perfusion

by
Reza Razavi
Biomedical Sciences Program

B.S. 1996, Montclair State University
M.S. 2001, Graduate School of Biomedical Sciences-UMDNJ


Thesis Advisor: Lawrence E. Harrison, M.D.

Associate Professor

Department of Surgery

Tuesday, June 30, 2009
Cancer Center, G-1196, 10:00 a.m.


Abstract

Subsets of patients with advanced gastrointestinal and gynecologic malignancies develop peritoneal carcinomatosis with a life expectancy of only 6 months. Systemic chemotherapy with curative intent for these patients has not been successful. Surgical cytoreduction followed by Hyperthermic Intraperitoneal Chemoperfusion (HIPEC) is an option for select patients with carcinomatosis of colorectal origin. Despite encouraging results, patients still recur after this aggressive therapy. Theoretically, hyperthermic treatments could possibly lead to thermotolerance, which may contribute to recurrences. One potential and novel strategy to improve clinical outcomes and to avoid thermotolerance is thermal sensitization through modulation of cellular reactive oxygen species (ROS). We have shown that induced oxidative stress through the addition of H2O2 under hyperthermic conditions increases tumor cell death in vitro. To extend these observations, we developed both a pre-clinical murine model of hyperthermic perfusion and a nude mouse model of peritoneal carcinomatosis from colon cancer cells of human origin. Using the in vivo Bioluminescence Imaging (BLI), we are able to evaluate and quantify this peritoneal tumor growth. By combining these two models, we show that normothermic saline perfusion (NTP) decreases tumor growth compared with no perfusion controls, and that tumor growth is further decreased with hyperthermic perfusion (HTP). The induction of oxidative stress with H2O2 in the perfusate at concentrations as high as 600 M is well tolerated in this model of hyperthermic perfusion. Importantly, induced oxidative stress under hyperthermic conditions (HTP + H2O2) dramatically decreases tumor cell growth compared to all other controls. Based on our observations, thermal sensitization through modulation of cellular ROS may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality. Moreover, this model would allow us to probe for other possible thermal sensitizing agents or the best combination of adjuvant therapies and to investigate other anticancer agents for treating peritoneal cancers originating from other primary tumors.


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