Effects of oxaliplatin and CPT-11 on cytotoxicity and nucleic acid incorporation of the fluoropyrimidines

Abstract

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 IC(10), IC(30), and IC(70) of oxaliplatin and CPT-11. Subsequently, cells were exposed for 24 h to IC(10), IC(30), and IC(70) of 5-FU, FUdR, and FUR. Cytotoxicity was measured by the MTT assay. Nucleic acid incorporation of [(3)H]fluoropyrimidine was then compared in the presence and absence of oxaliplatin or CPT-11 pretreatment.

Results: Synergistic cytotoxicity was displayed when IC(30) of oxaliplatin or CPT-11 was combined with IC(10) and IC(30) 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 IC(70). 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.

Fig. 1

Metabolic pathways for the fluoropyrimidines. FU, FUdR, and FUR are 5-fluorouracil, 5-fluoro-2’-deoxyuridine, and 5-fluorouridine, respectively. FdUMP is 5-fluoro-2’deoxyuridine-5’-monophosphate and FdUTP is 5-fluoro-2’deoxyuridine-5’-triphosphate. FUMP, FUDP, and FUTP are 5-fluorouridine-5’mono-, di-, and triphosphate, respectively. The enzyme thymidylate synthase is indicated by T.S. The dotted arrow displays the inhibitory action of FdUMP on T.S. activity