Amphotericin B as a potentiation agent to cytotoxic chemotherapy

Abstract

DEVELOPMENT of tumor cells resistant to chemotherapeutic drugs prevents the successful eradication of most human disseminated malignancies. Known mechanisms of drug resistance are many: defective drug transport, defective drug metabolism to active species, altered intracellular nucleotide pools, increased drug inactivation, altered DNA repair, gene amplification and altered target protein. Resistance to a given drug can result from several unrelated mechanisms. Moreover, resistance to a specific agent belonging to the groups of antitumor antibiotics or plant alkaloids can confer cross-resistance to structurally dissimilar drugs with different mechanisms of action. The pathway by which this pleiotropic resistance is acquired by tumor cells appears to be at the level of membrane transport. In membranes of hamster, mouse and human tumor cell lines that display multiple resistance to drugs, increased expression of a 170,000 dalton surface antigen has been shown to be correlated with resistance. A P-glycoprotein of identical molecular size, sharing some immunogenic homology with this membrane component, has been demonstrated in colchicine-resistant Chinese hamster ovarian cells. In these cells the colchicine resistance, the pleiotropic resistance and a reduced drug accumulation in the cells have been shown to be due to the same genetic alteration. The Pglycoprotein marker for drug resistance has also been demonstrated in the membrane of cells directly derived from ovarian cancer in two pati-