Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

Abstract

Several schedules of 5-fluorouracil (FU) and irinotecan (IRI) have been shown to improve overall survival in advanced colorectal cancer (CRC). Preclinical evidence suggests that the sequential administration of IRI and FU produces synergistic activity, although their clinical use has not been fully optimised. We investigated the interaction between short-term exposure to SN-38, the active metabolite of IRI, and prolonged exposure to FU in human CRC HT-29 cells and observed that the synergism of action between the two agents can be increased by extending the time of cell exposure to FU and reducing the interval between administration of the two agents. Based on these findings, we performed a phase I trial in 25 advanced CRC patients using a modified IRI/FU regimen as first-line therapy and evaluated three dose levels of IRI (150 -300 mg/m 2 ) and two of continuous infusion of FU (800 -1000 mg/m 2 ) in a 3-weekly schedule. The most severe grade III -IV toxicities were neutropoenia in four cycles and diarrhoea in three. One patient achieved complete response (4%), 12 a partial response (48%), the overall response rate was 52% (720, 95% CI); seven of 25 patients had stable disease (28%), the overall disease control was 80% (716, 95% CI). This modified IRI/FU schedule is feasible and exhibits potentially interesting clinical activity.

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

“…For example, low concentrations of cytarabine or topotecan have little effect on proliferation as single agents, but can dramatically antagonize eribulin activity under combination conditions. Indeed, this is not without precedent: antagonism has been observed for a variety of cancer drug combinations in preclinical studies, prompting follow up analyses to investigate both the mechanisms of the synergies as well as the effects of drug combination sequencing [28][29][30][31][32][33][34][35]. For instance, in one extensively studied example, the anthracycline doxorubicin antagonized activity of the vinca alkaloid vincristine in 83% (15/18) of hematopoietic cell lines tested.…”

Sorcin Induces a Drug-Resistant Phenotype in Human Colorectal Cancer by Modulating Ca2+ Homeostasis

“…Cell line authentication was done before starting this study by evaluating, respectively, the presence of a mutation in codon 13 of the ras proto-oncogene in HCT-116 cells, according to the ATCC product description, and the presence of the BRAF V600E mutation in HT-29 cells (26). HT-29 CRC cells resistant to single agents were selected as previously reported (27).…”

Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

“…8,10,[12][13][14][15][16] Therefore, we studied whether the antagonism between doxorubicin and VCR might be sequence dependent. Indeed, when VCR was given first, 1 day before doxorubicin, VCR induced significant apoptosis.…”

“…[8][9][10][11][12][13] Among others, sequence dependency was proven for the combination of asparaginase and methotrexate for anti-leukemia therapy. 8,10,[12][13][14][15][16] On a molecular level, the effects and signaling pathways induced by many chemotherapeutic drugs have not been analyzed in depth, and the consequences of their combinatorial application remain unclear. 17 As far as we know, no mechanistic data exist so far to explain the sequence dependency of any clinically proven drug combination on a molecular level.…”