peplomycin and Leukemia-L5178

Studying the treatment of NMRI mice with ip injections of bleomycin (BLM) for 5 days we found an approximate LD50 of 35 mg/kg; the toxicity of peplomycin (PEP) was slightly higher (LD50: approximately 25 mg/kg). The effect of the two drugs on growth of L5178y mouse lymphoma cells in NMRI mice was examined. BLM alone caused at a concentration of 2.5 mg/kg an almost complete inhibition of tumor cell growth; the same effect was determined with 1 mg PEP/kg. At these concentrations the drugs caused an increase of the survival time of 110% (BLM) or 104% (PEP). Given in combination, one-sixth of the optimal doses yielded an 100% increase of the median survival time. These results indicate a significant synergistic activity of the PEP-BLM combination on L5178y cell growth in vivo (FIC index: 0.34).

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cell Survival; Drug Synergism; Leukemia L5178; Leukemia, Experimental; Male; Mice; Peplomycin

Bleomycin (BLM) and pepleomycin (PEP) are two chemically related glycopeptide antitumor antibiotics which differ in their terminal residues only. Studying the growth-inhibitory potencies of BLM (clinical mixture), BLM-A2, BLM-B2 and PEP in the L5178y mouse lymphoma cell culture system, it was elucidated that the slopes of the dose-response curves at the ED50 concentration (around 1 microgram/ml) were steeper for PEP than for BLM. This result together with cytotoxicity determinations revealed a cytostatic action of PEP within a closer concentration range than BLM. Both drugs inhibit cell proliferation during S- and G2-phase. Given in combination, BLM and PEP inhibit cell proliferation in a highly significant synergistic way (FIC indexes: 0.25-0.46). This in vitro result, which might be of therapeutic importance, is correlated with differences on the molecular level. Determinations of the ratio between the number of single- and double-strand breaks in the DNA (the target molecule of the drugs) revealed a considerably lower value for DNA from BLM-treated cells (1.9:1) than for DNA from PEP-treated cells (13:1).

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Cell Division; Cells, Cultured; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Synergism; Interphase; Leukemia L5178; Leukemia, Experimental; Mice; Peplomycin

Topics: Animals; Biological Transport; Bleomycin; Cations, Divalent; Cobalt; Kinetics; Leukemia L5178; Leukemia, Experimental; Mice; Peplomycin; Structure-Activity Relationship