The anticancer agent, methylglyyoxal-bis (guanylhydrazone) (MGBG) has two major intracellular sites of action; inhibition of polyamine biosynthesis and interference with mitochondrial function. Of these, the latter is believed to be responsible for antiproliferative activity of the drug. Our studies with MGBG and studies by other laboratories with the highly specific inhibitor of polyamine biosynthesis, alpha-difluoromethylornithine (DFMO), indicate that mitochondrial function and polyamine biosynthesis, respectively, are critically involved in cell proliferation and that they represent reasonable sites for chemotherapeutic intervention. The potential of these sites, as demonstrated by the clinical usefulness of MGBG and DFMO, and their novelty among sites of action, known for other anticancer agents, provide sufficient cause for further investigation. The major objective of this proposal is to utilize MGBG and structurally or functionally-related drugs (particularly DFMO) to study mitochondrial function and polyamine biosynthesis in the context of cancer chemotherapy while gaining information relevant to the mechanism(s) of action of the drugs involved. In addition, polyamine uptake into normal and transformed cells, the structural specificity of the polyamine requirement in cell proliferation, anticancer drug action on mitochondrial function and biogenesis will be studied. In clinical studies, the usefulness of DFMO/MGBG sequential therapy on lymphoma and leukemia will be evaluated while monitoring a variety of experimental parameters relevant to patient responsiveness and drug action. Among the parameters that will be used in assessing drug effects are cell growth kinetics, ribonucleotide and plyamine pools size analysis by high pressure liquid chromatography, oxygen consumption studies of intact cells and isolated mitochondria, pyruvate utilization, synthesis of nuclear DNA by precursor incorporation using agarose gel electrophoresis and ornithine and S-adenosylmethionine decarboxylase activities by biochemical assay.
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