PREVENTION OF CHEMOTHERAPY-INDUCED OR X-IRRADIATION-INDUCED MONOCYTOPENIA BY ORAL-ADMINISTRATION OF LIPOPHILIC MURAMYL TRIPEPTIDE

Subsequent to systemic administration of doxoribicin or whole-body X-i rradiation, C57BL/6 mice exhibit a depletion in lymphoid cells (macrop hages) lasting 2-3 weeks and returning to normal by 4 weeks after eith er treatment. We evaluated the ability of repeated oral administration of the synthetic macrophage activator muramyl tripeptide phosphatidyl ethanolamine (MTP-PE), either in free form or encapsulated into multil amellar liposomes, to reverse or prevent the decline in macrophages af ter cytoreductive therapies. The number of both resident peritoneal ma crophages and peritoneal exudate cells elicited by thioglycollate-indu ced inflammation increased after the oral administration of MTP-PE (th ree times a week) for at least 3 weeks. The depletion of macrophage nu mber from the peritoneal cavity that occurred after two IV injections of doxorubicin or X-irradiation with 1.5 or 3.0 Gy was prevented by re peated oral feedings of MTP-PE. Moreover pretreatment of mice with ora l MTP-PE prevented depletion of macrophages resulting from IV injectio ns of doxorubicin. Modest protection was also noted for blood leukocyt es in mice receiving oral MTP-PE following systemic DXR. Similar effec ts were achieved when MTP-PE was encapsulated into phospholipid liposo mes: this formulation also allowed macrophages to be readily activated to the tumoricidal state. The oral administration of MTP-PE offers an additional strategy for protection of host defense cells during cytoa blative therapies.