Manish Patel1, Ram Agarwal, Bach Ardalan. 1. 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.
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.
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.
Authors: S Giacchetti; B Perpoint; R Zidani; N Le Bail; R Faggiuolo; C Focan; P Chollet; J F Llory; Y Letourneau; B Coudert; F Bertheaut-Cvitkovic; D Larregain-Fournier; A Le Rol; S Walter; R Adam; J L Misset; F Lévi Journal: J Clin Oncol Date: 2000-01 Impact factor: 44.544
Authors: P Rougier; E Van Cutsem; E Bajetta; N Niederle; K Possinger; R Labianca; M Navarro; R Morant; H Bleiberg; J Wils; L Awad; P Herait; C Jacques Journal: Lancet Date: 1998-10-31 Impact factor: 79.321
Authors: R Sanguedolce; G Vultaggio; F Sanguedolce; G Modica; F Li Volsi; G Diana; G Guereio; L Bellanca; L Rausa Journal: Anticancer Res Date: 1998 May-Jun Impact factor: 2.480