Purpose: The addition of oxaliplatin or CPT-11 to 5-FU has become common practice in the treatment of colorectal cancer. It is not known, however, which fluoropyrimidine drug (5-FU, FUdR, or FUR) will produce superior cytotoxicity when combined with either oxaliplatin or CPT-11. The purpose of the study was to determine the effects of oxaliplatin and CPT-11 on cytotoxicity and nucleic acid incorporation of all three fluoropyrimidines. Methods: HT-29 cells were exposed for 2 h to IC10, IC30, and IC70 of oxaliplatin and CPT-11. Subsequently, cells were exposed for 24 h to IC 10, IC30, and IC70 of 5-FU, FUdR, and FUR. Cytotoxicity was measured by the MTT assay. Nucleic acid incorporation of [ 3H]fluoropyrimidine was then compared in the presence and absence of oxaliplatin or CPT-11 pretreatment. Results: Synergistic cytotoxicity was displayed when IC30 of oxaliplatin or CPT-11 was combined with IC10 and IC30 of the fluoropyrimidines. One fluoropyrimidine did not achieve superior cytotoxicity over the others. After pretreatment with oxaliplatin or CPT-11, cytotoxic antagonism was observed as the concentration of a fluoropyrimidine increased up to IC70. The increasing cytotoxic antagonism correlated with decreases in fluoropyrimidine nucleic acid incorporation. The most significant incorporation difference existed within the 5-FU treated group. Conclusions: No single fluoropyrimidine is more cytotoxically effective over the others when combined with oxaliplatin or CPT-11. Correlation of cytotoxic antagonism to the inhibition of fluoropyrimidine nucleic acid incorporation implies difficulties in drug transport and/or metabolism only after oxaliplatin or CPT-11 pretreatment.
ASJC Scopus subject areas
- Cancer Research