ENHANCEMENT OF MACROPHAGE TUMOURICIDAL ACTIVITY BY THE ALKALOID DERIVATIVE UKRAIN. IN VITRO AND IN VIVO STUDIES.
SOTOMAYOR E.M.1, RAO K.1, LOPEZ D.M.1, LIEPINS A.2*
1) Department of Microbiology and Immunology, University
of Miami School of Medicine, Miami, Florida, USA.
2) Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6 Canada.
* Author to whom correspondence should be addressed.
Summary: Ukrain is a semisynthetic drug with immunomodulatory properties, derived from Chelidonium majus L. alkaloids and thiophosphoric acid. The effect of this compound on the growth of Balb/c syngenic mammary adenocarcinoma was assessed. Intravenous, but not subcutaneous or intraperitoneal, administration of this drug was found to be effective in delaying tumour growth in an actual therapeutic protocol initiated five days after tumour implantation. No untoward side-effects were observed using these in vivo treatment modalities. The role of macrophages in the observed retardation of tumour development was investigated using peritoneal exudate macrophages (PEM) in cytotoxicity assays. In previous studies, the authors have found that PEM of mammary tumour bearing mice lose their capacity to kill a variety of tumour target cells including the in vitro cultured homologous tumour cells (DA-3). Pretreatment of PEM from normal mice with 2.5 μΜ Ukrain for 24 h followed by stimulation with either INF-γ or with LPS + IFN-γ enhanced their cytotoxic activity. Treatment of PEM from tumour bearing mice with 2.5 μΜ Ukrain and LPS results in a reversal of their defective cytotoxic response against the DA-3 target cells. Furthermore, Ukrain alone, in the absence of a secondary signal, induced the activation of tumouricidal function of PEM from tumour bearing but not from normal mice. These data indicate that Ukrain's in vivo effects against the development of mammary tumours may be due, at least in part, to its ability to restore macrophage cytolytic function.