Membrane-to-membrane transfer of lipophilic drugs used against cancer or infectious disease.
Use of liposomal drug delivery systems can enhance the therapeutic potential of membrane active anti-cancer and anti-infectious drugs. Thus, the therapeutic index of the important antifungal agent amphotericin B is markedly improved via incorporation of the drug into liposomes. The mechanistic basis of this effect seems to be an increase in the selectivity of the drug at the cellular level. Thus, free amphotericin B can readily partition into both fungal and mammalian membranes and can cause toxicity to both types of cells, giving rise to the notorious in vivo toxicity of this drug. By contrast, when amphotericin B is formulated in certain types of liposomes, the drug still readily partitions into fungal membranes but can no longer partition into animal cell membranes, thus markedly reducing its toxicity. Liposomes can also be used to reduce the toxicity of membrane-active antitumor drugs. Thus, the peptide ionophore valinomycin is far less toxic to animals when presented in liposomal form. Nonetheless, the drug retains useful antitumor activity in this form. The underlying basis of the enhanced therapeutic index of liposomal valinomycin is unknown at this time but is being explored. The development of membrane-active anti-tumor drugs, in conjunction with liposomal delivery systems, could be an important new approach in cancer chemotherapy. While no anticancer drug is likely to be free of toxic side effects, the toxicities engendered by membrane-active antitumor drugs are likely to affect a different spectrum of tissues and organs than those caused by "conventional" antitumor drugs. Thus membrane-active drugs could complement existing drugs and provide a valuable adjunct to therapy.
Juliano
R L
RL
Department of Pharmacology, University of Texas Medical School, Houston 77096.
Daoud
S
S
Krause
H J
HJ
Grant
C W
CW
D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D002175:Candida / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D006461:Hemolysis / Q000187:drug effects; D007239:Infections / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008081:Liposomes / Q000008:administration & dosage*; D008855:Microscopy, Electron, Scanning; D012413:Rubidium / Q000378:metabolism; D012995:Solubility; D014634:Valinomycin / Q000627:therapeutic use*
D008081:Liposomes; D014634:Valinomycin; D000666:Amphotericin B; D012413:Rubidium