1-beta-D-arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy with cis-diamminedichloroplatinum(II) and modification of platinum-induced DNA interstrand cross-linking.
1-beta-D-Arabinofuranosylcytosine (ara-C) and hydroxyurea (HU) were investigated as possible inhibitors for the repair of cis-diamminedichloroplatinum(II) (DDP)-induced DNA damage. HU and ara-C were chosen for their known ability to inhibit DNA excision repair following UV irradiation. Work by several groups has suggested that the repair of DDP-induced DNA damage may involve an excision-repair mechanism. The cytotoxic effects of dose, exposure duration, and sequence for the three drugs was studied in a human colon cancer cell line (HT-29) by colony formation assays. Significant synergistic cytotoxicity was seen whether HU + ara-C were given prior to, or following DDP exposure. Cytotoxic synergy was also seen between HU + ara-C themselves. The effect of the combined antimetabolites on the level and persistence of DDP-induced DNA interstrand cross-links was assessed by DNA alkaline elution. These were measured as an indicator of DDP-DNA adduct formation and removal. When HU + ara-C exposure preceded or followed DDP treatment, higher levels of interstrand cross-linking were found at late time points than were seen with DDP alone, suggesting repair inhibition. We conclude that the combination of HU, ara-C, and DDP shows synergistic cytotoxicity, and that this effect may be due in part to inhibition of DDP-induced DNA adduct repair. The concentrations of drugs used in vitro are achievable in humans. On the basis of these results, a Phase I/II clinical trial of the three agents in combination has been initiated.
Swinnen
L J
LJ
Department of Medicine, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153.
Barnes
D M
DM
Fisher
S G
SG
Albain
K S
KS
Fisher
R I
RI
Erickson
L C
LC
D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D003561:Cytarabine / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004357:Drug Synergism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003561:Cytarabine; D004247:DNA; D002945:Cisplatin; D006918:Hydroxyurea