Abstract
1-β-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.
Original language | English (US) |
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Pages (from-to) | 1383-1389 |
Number of pages | 7 |
Journal | Cancer Research |
Volume | 49 |
Issue number | 6 |
State | Published - Mar 15 1989 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Cancer Research