Membrane active drugs such as ionophores are potentially useful cytotoxic agents for therapy of cancer and of infectious disease. However, ionophores have not been widely used therapeutically because of their extreme host toxicity. Recently we demonstrated that the toxicity of the ionophoric anti fungal drug amphotericin B could be dramatically reduced, with no loss of therapeutic potency, by incorporation of the drug in lipid vesicles (liposomes). We further showed that amphotericin B would selectively transfer from liposomes to fungal cells but not to mammalian cells; this selective transfer is persumably one basis for the enhanced therapeutic index of liposomal amphotericin B. In this proposal we define two distinct goals. The first is to fully elucidate the biophysical and cellular bases for the selective toxicity and enhanced therapeutic profile of liposomal amphotericin B. To this end we will explore liposom membrane parameters, including fluidity, charge, size and drug/lipid ratio, which govern the parameters with toxicity to host cells both in vitro and in vivo. The second goal is to extend the concepts developed with liposomal amphotericin B to the deployment of inophores as anti tumor agents. We have demonstrated a reduction in the host toxicity of valinomycin with maintainance/enhancement of anti tumor effects in P388 leukemia, using liposomes. We now intend to a) explore the cellular basis of action of liposomal valinomycin; b) evaluate liposomal valinomycin in other tumor systems, especially solid tumors; c) study the distribution and pharmacokinetics of liposomal valinomycin; d) look for synergisms between valinomycin and """"""""conventional"""""""" anti tumor drugs; e) explore the use of other inophores in liposomal form as anti tumor agents. If successful, these studies may open a path toward utilizing a wide variety of membrane active drugs as chemotherapeutic agents.
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