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

We determined the therapeutic effect of irinotecan (CPT-11) combined with t he immunomodulator JET 3002, a synthetic bacterial lipopeptide (N-acylated derivative of psi-amino-C1-C3-alkane-sulfonic acid), against highly metasta tic human pancreatic carcinoma cells injected into the pancreas of athymic nude mice. Mice received four courses consisting of three daily oral doses of JET 3002, followed by once weekly i.p. injection of CPT-II, Control mice were treated with CPT-11 alone, JET 3002 alone, or saline. Tumor growth an d metastasis were assessed by gross pathology and confirmed by histological examination. Treatment with CPT-II alone significantly decreased the media n volume of pancreatic tumors and the incidence of metastasis, whereas trea tment with only JET 3002 did not. The combination therapy of CPT-II plus JE T 3002 decreased tumor volume and incidence of metastasis significantly mor e than CPT-11 alone. The number of apoptotic cells (terminal deoxynucleotid yl transferase-mediated nick end labeling assay), the number of scavenger-r eceptor-positive macrophages, and expression level of inducible nitric oxid e synthase (iNOS) within lesions directly correlated with therapeutic effec ts. Indeed, the in vitro incubation of tumor cells with macrophages activat ed by JET 3002 plus IFN-gamma produced a significant lysis of tumor cells t hat could he blocked by a specific inhibitor of iNOS. Collectively, these d ata demonstrate that the oral administration of the immunomodulator JET 300 2 combined with i.p. injection of CPT-11 can decrease the growth of human p ancreatic carcinoma and the incidence of metastasis in nude mice by both a direct antitumor effect and the activation of iNOS in infiltrating macropha ges.