amphotericin-b and Leukemia-P388

Topics: Amphotericin B; Animals; Antifungal Agents; Ciguatoxins; Dinoflagellida; Ethers; Ethers, Cyclic; Leukemia P388; Mice; Microbial Sensitivity Tests

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.

Topics: Amphotericin B; Animals; Candida; Cell Membrane; Chemistry, Pharmaceutical; Hemolysis; Infections; Kidney; Leukemia P388; Leukemia, Experimental; Liposomes; Microscopy, Electron, Scanning; Rubidium; Solubility; Valinomycin

In this study, we report that membrane-active agents can reverse or circumvent multidrug resistance in tumor cells through alteration of membrane permeability. Two different cell lines are used to assay the drug-sensitivity: colchicine-resistant clone derived from human cancer KB cell line with multidrug resistance and P388 leukemia cells resistant to many anticancer agents such as adriamycin, vincristine and other agents. In the latter system, circumvention effect can be tested with mice bearing drug-sensitive or -resistant P388 leukemia in vivo. Thioridazine (calmodulin inhibitor), N-(p-methylbenzyl)decaprenylamine, N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine and amphotericin B (a sterol-binding polyene antibiotic) have been screened with these two drug-resistant cell systems. They overcome the multidrug resistance in Chr-24 as well as P388 leukemia cells resistant to adriamycin or vincristine. N-solanesyl-N,N'-bis(3,4-dimethoxylbenzyl)ethylenediamine can reverse the drug-resistance in vivo against mice bearing resistant leukemia. Mechanism to reverse the drug-resistance is to be discussed in relation with altered membrane permeability of the anticancer agents.

Topics: Amphotericin B; Animals; Antineoplastic Agents; Butadienes; Calcium Channel Blockers; Calmodulin; Cell Line; Cell Membrane Permeability; Drug Resistance; Drug Synergism; Hemiterpenes; Humans; KB Cells; Leukemia P388; Pentanes; Thioridazine

4,4'-(3,7,12,16-Tetramethyl-1,3,5,7,9,11,13,15,17-octadecanonaen-1 ,18-diyl) bis (1-ethylpyridinium) dibromide (Y-18598), a novel carotenoid analog with 1-ethylpyridine rings as terminal groups, was found to be effective against P388 leukemia which was refractory to amphotericin B and retinoic acid used as representatives of polyene-containing drugs. The life span of leukemic mice was increased by 56% over the control following administration of 2.5 mg/kg on days 1-5. Among these polyene-containing compounds, Y-18598 was the most highly cytotoxic to P388 leukemia cells in vitro.

Topics: Amphotericin B; Animals; Antineoplastic Agents; Carotenoids; Female; Glucose; Leukemia P388; Leukemia, Experimental; Macrophages; Mice; Mice, Inbred Strains; Tretinoin

In Adriamycin-sensitive and -resistant P388 cells, coincubation with amphotericin B causes a marked increase in Adriamycin retention, as determined by laser flow cytometry. P388/S cells were generally more affected than were P388/R cells. Preincubation with amphotericin B had a greater effect on Adriamycin retention than did co- or postincubation. In splenocytes, bone marrow, and ascites from mice, enhanced Adriamycin retention was seen in all the tissues. However, bone marrow cells showed heterogeneous response, with some populations being more sensitive than others.

Topics: Amphotericin B; Animals; Biological Transport; Cell Division; Cells, Cultured; Doxorubicin; Fluorometry; Lasers; Leukemia P388; Leukemia, Experimental; Mice; Phenothiazines