Abstract
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.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer with an incidence of1.8 million cases in 2018, which is expected to reach approximately 2.2 million worldwide by 2030 [1].With a mortality rate of 700,000 patients per year worldwide, it has the fourth most cancer-related deaths [2,3]
Dose-response curves for each drug were established in four human CRC cell lines (DLD1, HCT116, SW620, and LS174T)
Drug activities were compared by measuring the cell metabolic activity, presented as % of control, which indirectly corresponds to cell viability
Summary
With a mortality rate of 700,000 patients per year worldwide, it has the fourth most cancer-related deaths [2,3]. The 5-year survival rate is 21% for all races in late-stage CRC, compared to 65% in early-stage diagnosis [4]. The choice of current clinical management of CRC depends on the stage of the disease, the molecular analysis of the tumor, i.e., microsatellite instability, KRAS and BRAF mutations [5,6], as well as the health status of the patient [7]. Molecules 2020, 25, 2614 undergo surgical resection. Late-stage or metastatic lesions very often cannot be removed by surgical resection and patients generally receive chemotherapy, applied as a combinatory treatment [8]
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