In vivo modulation of macrophage tumoricidal activity by oral administration of the liposome-encapsulated macrophage activator CGP 19835A.
The present study evaluated the in vivo biological activity of synthetic muramyl tripeptide, CGP 19835A, when encapsulated into phosphatidylcholine liposomes (POPC-19835A) and administered as an p.o. immunomodulator to BALB/c mice. Liposomes were rapidly absorbed in the intestine and reached the systemic circulation within 4 h. Alveolar macrophages harvested from the lungs of mice 24 h after a single p.o. feeding of POPC-19835A were tumoricidal toward syngeneic murine renal cell carcinoma target cells. Repeated daily feedings with POPC-19835A generated sustained activation of the alveolar macrophages. Activation of peritoneal macrophages to the tumoricidal state required at least three daily feedings of POPC-19835A. In vitro studies demonstrated the release of tumor necrosis factor alpha and interleukin 6 by macrophages activated by POPC-19835A in the presence of gamma-interferon. Interleukin 1 and nitric oxide were not induced in macrophages by this liposomal preparation. Daily administration of POPC-19835A after i.v. injection of renal cell carcinoma tumor in BALB/c mice inhibited the development of experimental lung metastasis and confirmed the potential role of long-term therapy with this new p.o. immunomodulator.
Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
S
S
Tanguay
C D
CD
Bucana
M R
MR
Wilson
I J
IJ
Fidler
A C
AC
von Eschenbach
J J
JJ
Killion
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000230:Adenocarcinoma / Q000628:therapy*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D004337:Drug Carriers; D005260:Female; D007167:Immunotherapy; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000628:therapy*; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D007375:Interleukin-1; D015850:Interleukin-6; D008081:Liposomes; D010714:Phosphatidylethanolamines; D014409:Tumor Necrosis Factor-alpha; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine