SYNERGISTIC CYTOTOXICITY OF CARBOPLATIN AND DIVICINE ON MURINE ERYTHROLEUKEMIC CELLS

Carboplatin (CBDCA) and the pyrimidine aglycone divicine displayed cyt otoxic effects on murine erythroleukemic cells (MELC), with ID50 value s of 158 and 37 mu M, respectively. Combination of CBDCA and divicine, at a 2:1 ratio, increased cytotoxicity considerably. Under specific c onditions of time schedule of administration, the association of CBDCA and divicine resulted in a clear synergistic activity. Alkaline eluti on studies on both unirradiated and gamma-irradiated MELC demonstrated opposite patterns of DNA damage with the two molecules. Thus, CBDCA e licited DNA interstrand crosslinks (ISC), while divicine resulted in D NA single strand breaks (SSB). Association of both molecules led in th e unirradiated cells to a higher SSB frequency than recorded with divi cine alone. Accordingly, intracellular activation of CDBCA by redox cy cling of divicine seems not to be involved. Rather, intracellular plat inum appears to enhance cytotoxicity of divicine. (C) 1994 Academic Pr ess, Inc.