Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

The combination of 5-fluorouracil-folinic acid and oxaliplatin has led to a significant improvement of chemotherapy efficacy in advanced pretreated colorectal cancer. The objective of the present study was, considering the oxaplatin-5-fluorouracil-folinic acid combination, to examine the impact of o...

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Bibliographic Details
Published in:British journal of cancer Vol. 86; no. 7; pp. 1162 - 1168
Main Authors: FISCHEL, J. L, FORMENTO, P, CICCOLINIL, J, ROSTAGNO, P, ETIENNE, M. C, CATALIN, J, MILANO, G
Format: Journal Article
Language:English
Published: Basingstoke Nature Publishing Group 08-04-2002
Subjects:
Acids
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Cancer research
Cancer therapies
Cell Cycle
Cell Membrane
Chemotherapy
Colonic Neoplasms - pathology
Colorectal cancer
Cytotoxicity
DNA Damage
Drug Administration Schedule
Drug Interactions
Drugs
Experimental Therapeutics
Fluorouracil - administration & dosage
Fluorouracil - pharmacokinetics
Fluorouracil - pharmacology
General aspects
Humans
Leucovorin - administration & dosage
Medical prognosis
Medical research
Medical sciences
Organoplatinum Compounds - administration & dosage
Organoplatinum Compounds - pharmacokinetics
Organoplatinum Compounds - pharmacology
Oxaliplatin
Permeability
Pharmacology. Drug treatments
Response rates
Thymidylate Synthase - pharmacology
Toxicity Tests
Tumor Cells, Cultured
France
Antineoplastic agent
Rectal disease
Calcium folinate
Oxaliplatin
Intestinal disease
Drug interaction
Colon
Fluorouracil
Platinum II Complexes
Human
Drug combination
Enzyme
Transferases
Fluoropyrimidine derivatives
Enzyme inhibitor
Malignant tumor
Thymidylate synthase
In vitro
Biological activity
Colonic disease
Methyltransferases
Antimetabolic
Cell death
Rectum
Digestive diseases
Pyrimidine derivatives
Intracellular
Apoptosis
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Summary:The combination of 5-fluorouracil-folinic acid and oxaliplatin has led to a significant improvement of chemotherapy efficacy in advanced pretreated colorectal cancer. The objective of the present study was, considering the oxaplatin-5-fluorouracil-folinic acid combination, to examine the impact of one given drug on the cellular determinants of cytotoxic activity of the other drug. These cellular factors were analysed on the human colon cancer cell line WiDr in clinically relevant conditions of drug exposure ('De Gramont' schedule) with oxaliplatin-folinic acid during 2 h followed by 5-fluorouracil 48 h. The DNA binding of oxaliplatin was significantly reduced by the presence of 5-fluorouracil but this effect was time-dependent and after 50 h the platinum incorporated into DNA was identical in controls and in the drug combination. In the presence of oxaliplatin, there was less formation of FUH(2) which is the first catabolite produced in the cascade of 5-fluorouracil metabolic degradation. The effects of drugs on cell cycle were quite different from one drug to the other with oxaliplatin inducing a shift towards G(2) accumulation and 5-fluorouracil-folinic acid to a greater proportion of cells in G(1)-S. When oxaliplatin and 5-fluorouracil-folinic acid were combined the cell cycle effects were very similar to that of the 5-fluorouracil-folinic acid sequence alone. Oxaliplatin was able to reduce thymidylate synthase activity with a marked impact 28 h after the beginning of cell exposure to the drug. The 5-fluorouracil-folinic acid drug sequence led to a profound reduction in thymidylate synthase activity and this decrease was not markedly enhanced by the presence of oxaliplatin. Regarding apoptosis, changes in mitochondrial membrane permeability were observed in the presence of the tested drugs and the impact of 5-fluorouracil-folinic acid was greater than that of oxaliplatin. The addition of oxaliplatin did not amplify the action of 5-fluorouracil-folinic acid upon mitochondrial membrane permeability change. The presence of oxaliplatin itself did not modify the intracellular concentration of total reduced folates. The fact that oxaliplatin may reduce 5-fluorouracil catabolism could be central in explaining the supra-additive interaction between these drugs.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6600185