Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362.
The purpose of this study was to determine whether the activation of inducible nitric oxide synthase (iNOS) can serve as a target for immunotherapeutic agents for treatment of murine reticulum cell sarcoma metastases. Liver metastases were established by the i.v. injection of M5076 cells into syngeneic C57BL/6 mice. Multiple systemic administrations of multilamellar vesicle-liposomes (MLV) containing the lipopeptide CGP 31362 (MLV-31362) or MLV-31362 combined with murine IFN-gamma eradicated the metastases. Tumor regression correlated with iNOS expression within the tumor lesions detected by Northern blot and immunohistochemistry techniques and with increased production of nitric oxide (NO). The administration of a specific iNOS inhibitor, NG-methyl-L-arginine, significantly decreased NO production and diminished the antitumor activities of the immunomodulators. Consistent with the regression of hepatic metastases, the combination of MLV-31362 and IFN-gamma synergistically induced iNOS gene expression, NO production, and apoptosis in the tumor cells under in vitro and in vivo conditions. The addition of NMA prevented the production of NO and apoptosis. These data imply that multiple systemic administrations of MLV-31362 plus IFN-gamma activate endogenous iNOS in sarcoma cells, which then undergo apoptosis, leading in turn to the regression of M5076 sarcoma hepatic metastases.
Xie
K
K
Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Huang
S
S
Dong
Z
Z
Gutman
M
M
Fidler
I J
IJ
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004337:Drug Carriers; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology; D008081:Liposomes; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000556:secondary; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000097:blood; D009842:Oligopeptides / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine
D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D008081:Liposomes; D009566:Nitrates; D009573:Nitrites; D009842:Oligopeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; C068423:CGP 31362; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases