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Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

1
Molecular Pharmacology Group, School of Pharmaceutical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland
2
Translational Research Center in Oncohaematology, University of Geneva, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2020, 25(11), 2614; https://doi.org/10.3390/molecules25112614
Received: 3 May 2020 / Revised: 30 May 2020 / Accepted: 1 June 2020 / Published: 4 June 2020
The combination of folinic acid, 5-fluorouracil, oxaliplatin and/or irinotecan (FOLFOXIRI) is the standard of care for metastatic colorectal cancer (CRC). This strategy inhibits tumor growth but provokes drug resistance and serious side effects. We aimed to improve FOLFOXIRI by optimization of the dosing and the sequence of drug administration. We employed an orthogonal array composite design and linear regression analysis to obtain cell line-specific drug combinations for four CRC cell lines (DLD1, SW620, HCT116, LS174T). Our results confirmed the synergy between folinic acid and 5-fluorouracil and additivity, or even antagonism, between the other drugs of the combination. The drug combination administered at clinical doses resulted in significantly higher antagonistic interactions compared to the low-dose optimized drug combination (ODC). We found that the concomitant administration of the optimized drug combination (ODC) was comparatively active to sequential administration. However, the administration of oxaliplatin or the active metabolite of irinotecan seemed to sensitize the cells to the combination of folinic acid and 5-fluorouracil. ODCs were similarly active in non-cancerous cells as compared to the clinically used doses, indicating a lack of reduction of side effects. Interestingly, ODCs were inactive in CRC cells chronically pretreated with FOLFOXIRI, suggesting the occurrence of resistance. We were unable to improve FOLFOXIRI in terms of efficacy or specificity. Improvement of CRC treatment should come from the optimization of targeted drugs and immunotherapy strategies. View Full-Text
Keywords: colorectal carcinoma (CRC); drug-drug interaction; optimized drug combination; treatment schedule; synergy colorectal carcinoma (CRC); drug-drug interaction; optimized drug combination; treatment schedule; synergy
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MDPI and ACS Style

Zoetemelk, M.; Ramzy, G.M.; Rausch, M.; Nowak-Sliwinska, P. Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment. Molecules 2020, 25, 2614. https://doi.org/10.3390/molecules25112614

AMA Style

Zoetemelk M, Ramzy GM, Rausch M, Nowak-Sliwinska P. Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment. Molecules. 2020; 25(11):2614. https://doi.org/10.3390/molecules25112614

Chicago/Turabian Style

Zoetemelk, Marloes, George M. Ramzy, Magdalena Rausch, and Patrycja Nowak-Sliwinska. 2020. "Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment" Molecules 25, no. 11: 2614. https://doi.org/10.3390/molecules25112614

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