g(m1)-ganglioside and Leukemia-P388

Prolonged exposure to vincristine correlates with improved therapeutic activity. In this work, two methods are used to increase the circulation longevity of liposomal formulations of vincristine. The first involves incorporation of the ganglioside GM1, which acts to increase the circulation longevity of liposomal carriers, while the second approach relies on a modification of the vincristine encapsulation procedure which enhances drug retention. It is shown that these approaches are synergistic and increase the circulation half-life of vincristine from approximately 1 h to greater than 12 h. This results in a dramatic improvement in the therapeutic activity of liposomal vincristine as measured using a murine P388 lymphocytic leukemia model. At doses above 2 mg/kg, the optimized liposomal vincristine formulation cures greater than 50% of mice bearing the P388 tumor, whereas free vincristine results in no cures.

Topics: Animals; Drug Carriers; Drug Combinations; Drug Screening Assays, Antitumor; Female; G(M1) Ganglioside; Hydrogen-Ion Concentration; Leukemia P388; Liposomes; Mice; Vincristine

This study was undertaken in an attempt to understand the mechanism of antitumor action of pyrimidinones alone and in combination with cyclophosphamide (CY). Pyrimidinones such as 2-amino-5-bromo-6-(3-fluorophenyl)-4(3H)pyrimidinone (ABMFPP) were relatively nontoxic toward murine L1210 leukemia cell growth in vitro with the concentration of drug required for a 50% inhibition of cell growth being greater than 50 micrograms/ml. In contrast, ABMFPP showed anti-B16 melanoma activity in vivo which was sensitive to X-irradiation of the hosts. These results collectively suggest that pyrimidinones may act differently from conventional cytotoxic antitumor agents. Multiple i.p. injections of ABMFPP (125 mg/kg/injection) significantly augmented the cytotoxicity of both natural killer cells and macrophages in peritoneal exudates. The augmentation of both effector cell populations was delayed, but was more pronounced when animals received a dose of CY (100 mg/kg) prior to ABMFPP injections. The combination of CY and ABMFPP also showed a synergistic anti-P388 leukemia effect which appeared to be related to the initial reduction of the tumor burden by CY and the marked augmentation of the cytotoxicity of both natural killer cells and macrophages by ABMFPP. The antitumor activity of ABMFPP against B16 melanoma was almost completely eliminated when animals received a dose of 400 rads X-irradiation 5 days prior to tumor inoculation or a dose of 200 rads X-irradiation followed by several injections of anti-asialo monosialoganglioside antibody. The administration of anti-asialo monosialoganglioside alone also markedly reduced the anti-B16 melanoma activity of ABMFPP. The magnitude of reduction of the antitumor effect of ABMFPP by radiation and/or anti-asialo monosialoganglioside antibody directly correlated with the inhibition of the ABMFPP-mediated augmentation of immune responses. These results strongly suggest that the antitumor effect of ABMFPP alone or in combination with CY is at least in part mediated through its augmentation of natural killer cell and/or macrophage activities.

Topics: Animals; Antibodies; Cell Division; Cyclophosphamide; Cytosine; G(M1) Ganglioside; Glycosphingolipids; Killer Cells, Natural; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Macrophages; Melanoma; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA