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

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.