Synergistic cytotoxicity of carboplatin and divicine on murine erythroleukemic cells.
Carboplatin (CBDCA) and the pyrimidine aglycone divicine displayed cytotoxic effects of murine erythroleukemic cells (MELC), with ID50 values of 158 and 37 microM, respectively. Combination of CBDCA and divicine, at a 2:1 ratio, increased cytotoxicity considerably. Under specific conditions of time schedule of administration, the association of CBDCA and divicine resulted in a clear synergistic activity. Alkaline elution studies on both unirradiated and gamma-irradiated MELC demonstrated opposite patterns of DNA damage with the two molecules. Thus, CBDCA elicited DNA interstrand crosslinks (ISC), while divicine resulted in DNA single strand breaks (SSB). Association of both molecules led in the unirradiated cells to a higher SSB frequency than recorded with divicine alone. Accordingly, intracellular activation of CDBCA by redox cycling of divicine seems not to be involved. Rather, intracellular platinum appears to enhance cytotoxicity of divicine.
Tonetti
M
M
Institute of Biochemistry, University of Genoa, Italy.
Sturla
L
L
Bistolfi
T
T
Benatti
U
U
De Flora
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016190:Carboplatin / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005720:Gamma Rays; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute; D051379:Mice; D011744:Pyrimidinones / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011744:Pyrimidinones; C026511:divicine; D016190:Carboplatin