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 the immunomodulator JBT 3002, a synthetic bacterial lipopeptide (N-acylated derivative of psi-amino-C1-C3-alkane-sulfonic acid), against highly metastatic human pancreatic carcinoma cells injected into the pancreas of athymic nude mice. Mice received four courses consisting of three daily oral doses of JBT 3002, followed by once weekly i.p. injection of CPT-11. Control mice were treated with CPT-11 alone, JBT 3002 alone, or saline. Tumor growth and metastasis were assessed by gross pathology and confirmed by histological examination. Treatment with CPT-11 alone significantly decreased the median volume of pancreatic tumors and the incidence of metastasis, whereas treatment with only JBT 3002 did not. The combination therapy of CPT-11 plus JBT 3002 decreased tumor volume and incidence of metastasis significantly more than CPT-11 alone. The number of apoptotic cells (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), the number of scavenger-receptor-positive macrophages, and expression level of inducible nitric oxide synthase (iNOS) within lesions directly correlated with therapeutic effects. Indeed, the in vitro incubation of tumor cells with macrophages activated by JBT 3002 plus IFN-gamma produced a significant lysis of tumor cells that could be blocked by a specific inhibitor of iNOS. Collectively, these data demonstrate that the oral administration of the immunomodulator JBT 3002 combined with i.p. injection of CPT-11 can decrease the growth of human pancreatic carcinoma and the incidence of metastasis in nude mice by both a direct antitumor effect and the activation of iNOS in infiltrating macrophages.
Bruns
C J
CJ
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Shinohara
H
H
Harbison
M T
MT
Davis
D W
DW
Nelkin
G
G
Killion
J J
JJ
McConkey
D J
DJ
Dong
Z
Z
Fidler
I J
IJ
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D020287:In Situ Nick-End Labeling; D015552:Injections, Intralesional; D000077146:Irinotecan; D055666:Lipopeptides; D008074:Lipoproteins / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000276:Adjuvants, Immunologic; D000972:Antineoplastic Agents, Phytogenic; C112524:JBT-3002; D055666:Lipopeptides; D008074:Lipoproteins; D018809:Proliferating Cell Nuclear Antigen; D000077146:Irinotecan; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D002166:Camptothecin