Clinical Cancer Research, Vol 4, Issue 9 2053-2063, Copyright © 1998 by American Association for Cancer Research

ARTICLES

Prevention of intestinal toxic effects and intensification of irinotecan's therapeutic efficacy against murine colon cancer liver metastases by oral administration of the lipopeptide JBT 3002

H Shinohara, JJ Killion, H Kuniyasu, R Kumar and IJ Fidler
Department of Cell Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

The induction of severe diarrhea limits the usefulness of the DNA topoisomerase I inhibitor irinotecan (CPT-11) in the treatment of advanced colon cancer. We investigated whether oral administration of the new synthetic bacterial lipopeptide, JBT 3002, encapsulated in phospholipid liposomes could prevent damage to the intestinal epithelium and lamina propria and thus allow for the parenteral administration of high-dose irinotecan to mice with established syngeneic CT-26 colon cancer liver metastases. Treatment of mice with four daily i.p. injections of 100 mg/kg irinotecan was effective against liver metastases but also resulted in loss of body weight and early death. Histopathological examination of the intestines after this treatment revealed loss of villi, epithelial vacuolation, decrease in the number of cells in the crypts in S-phase, increase in the number of apoptotic cells, and reduction in the number of lymphocytes in the lamina propria. In contrast, treatment of mice with the same irinotecan regimen after oral administration of JBT 3002 produced highly significant inhibition of liver metastases without detectable damage to the intestines. Studies that used irinotecan administered once a week for 3 weeks after pretreatment with oral JBT 3002 demonstrated significantly intensified eradication of established CT-26 liver metastases compared with treatment with once-weekly irinotecan alone. Histological studies revealed that the liver metastases in mice treated with oral JBT 3002 and i.p. irinotecan contained a higher number of macrophages than metastases in mice treated with either drug alone. In vitro studies revealed that irinotecan produced direct antiproliferative effects but JBT 3002 did not. Tumor cells exposed to both irinotecan and macrophages activated by JBT 3002 were highly susceptible to lysis. These data show that oral administration of JBT 3002 can prevent irinotecan-induced gastrointestinal toxic effects and maintain the integrity of the lamina propria, thus allowing for intensification of irinotecan therapy against liver metastases from colon cancer.

This article has been cited by other articles:

				G. Brandi, J. Dabard, P. Raibaud, M. Di Battista, C. Bridonneau, A. M. Pisi, A. M. M. Labate, M. A. Pantaleo, A. De Vivo, and G. Biasco Intestinal Microflora and Digestive Toxicity of Irinotecan in Mice Clin. Cancer Res., February 15, 2006; 12(4): 1299 - 1307. [Abstract] [Full Text] [PDF]

				J. Zhao, L. Huang, N. Belmar, R. Buelow, and T. Fong Oral RDP58 Allows CPT-11 Dose Intensification for Enhanced Tumor Response by Decreasing Gastrointestinal Toxicity Clin. Cancer Res., April 15, 2004; 10(8): 2851 - 2859. [Abstract] [Full Text] [PDF]

				T. Ikegami, L. Ha, K. Arimori, P. Latham, K. Kobayashi, S. Ceryak, Y. Matsuzaki, and B. Bouscarel Intestinal Alkalization As a Possible Preventive Mechanism in Irinotecan (CPT-11)-induced Diarrhea Cancer Res., January 1, 2002; 62(1): 179 - 187. [Abstract] [Full Text] [PDF]

				F. Zhang, G. Zhao, and Z. Dong Phosphatidylcholine-specific phospholipase C regulates activation of RAW264.7 macrophage-like cells by lipopeptide JBT3002 J. Leukoc. Biol., June 1, 2001; 69(6): 1060 - 1066. [Abstract] [Full Text] [PDF]

				R. P. Boushey, B. Yusta, and D. J. Drucker Glucagon-like Peptide (GLP)-2 Reduces Chemotherapy-associated Mortality and Enhances Cell Survival in Cells Expressing a Transfected GLP-2 Receptor Cancer Res., January 1, 2001; 61(2): 687 - 693. [Abstract] [Full Text]

				S. Yano, H. Shinohara, R. S. Herbst, H. Kuniyasu, C. D. Bucana, L. M. Ellis, D. W. Davis, D. J. McConkey, and I. J. Fidler Expression of Vascular Endothelial Growth Factor Is Necessary but not Sufficient for Production and Growth of Brain Metastasis Cancer Res., September 1, 2000; 60(17): 4959 - 4967. [Abstract] [Full Text]

				H. Shinohara, S. Yano, C. D. Bucana, and I. J. Fidler Induction of Chemokine Secretion and Enhancement of Contact-Dependent Macrophage Cytotoxicity by Engineered Expression of Granulocyte-Macrophage Colony-Stimulating Factor in Human Colon Cancer Cells J. Immunol., March 1, 2000; 164(5): 2728 - 2737. [Abstract] [Full Text] [PDF]

				C. J. Bruns, H. Shinohara, M. T. Harbison, D. W. Davis, G. Nelkin, J. J. Killion, D. J. McConkey, Z. Dong, and I. J. Fidler Therapy of Human Pancreatic Carcinoma Implants by Irinotecan and the Oral Immunomodulator JBT 3002 Is Associated with Enhanced Expression of Inducible Nitric Oxide Synthase in Tumor-infiltrating Macrophages Cancer Res., January 1, 2000; 60(1): 2 - 7. [Abstract] [Full Text]

				H. Shinohara, J. J. Killion, C. D. Bucana, S. Yano, and I. J. Fidler Oral Administration of the Immunomodulator JBT-3002 Induces Endogenous Interleukin 15 in Intestinal Macrophages for Protection against Irinotecan-mediated Destruction of Intestinal Epithelium Clin. Cancer Res., August 1, 1999; 5(8): 2148 - 2156. [Abstract] [Full Text] [PDF]