Effects of oxaliplatin and CPT-11 on cytotoxicity and nucleic acid incorporation of the fluoropyrimidines.
OBJECTIVE
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.
Patel
Manish
M
Division of Hematology and Oncology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, 1475 NW 12th Avenue, (D8-4) Rm. 3510, Miami, FL 33136, USA.
Agarwal
Ram
R
Ardalan
Bach
B
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D005467:Floxuridine / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D009696:Nucleic Acids / Q000187:drug effects* / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D014529:Uridine / Q000031:analogs & derivatives* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D009696:Nucleic Acids; D009944:Organoplatinum Compounds; D005467:Floxuridine; D000077150:Oxaliplatin; C001943:5-fluorouridine; D000077146:Irinotecan; D005472:Fluorouracil; D014529:Uridine; D002166:Camptothecin