The effect of 5-fluorouracil on cisplatin induced DNA interstrand cross-linking in a mouse ascites tumor growing in vivo

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Abstract
In earlier studies we showed that a supra-additive cytotoxic effect was obtained with combined treatment with cisplatin and 5-fluorouracil (5-FU) of Bp8 ascites tumor growing in vivo in mice. We therefore studied the DNA interstrand cross-linking after single drug treatment with cisplatin, 5-FU and the drugs combined. The alkaline elution technique was used. 5-FU induced no measurable DNA cross-linking. Cisplatin caused a dose-dependent increase in DNA cross-links 6 h after treatment. When combining cisplatin and 5-FU, no significant change in the number of DNA cross-links was found for this time. The removal of DNA interstrand cross-links was studied after 24 and 36 h. There was no difference in the removal rate between single drug treatment with cisplatin as compared with the combined treatment with the two drugs. Also, the number of DNA single strand breaks (SSB) possibly created when the cisplatin induced cross-links or UV-induced DNA damage were repaired were measured with the alkaline elution technique. No increase in the amount of SSB was seen after combined treatment. Thus, we found no interaction of 5-FU and cisplatin in terms of DNA damage. Other mechanisms for the supra-additive effect found when combining cisplatin and 5-FU have to be considered.

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