Sequence-dependent growth inhibition and DNA damage formation by the irinotecan–5-fluorouracil combination in human colon carcinoma cell lines

Mans, Dennis R.A.; Grivicich, Ivana; Peters, Godefridus J.; Schwartsmann, Gilberto

doi:10.1016/s0959-8049(99)00222-1

Cited by 93 publications

(63 citation statements)

References 29 publications

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“…Furthermore, increased DNA damage was also observed in SW620 and HT-29 colon carcinoma cells when cells were pre-exposed to IRI before FU (Mans et al, 1999). These results are in agreement with our findings that the sequential exposure of colon carcinoma cells to SN-38 before FU produces a significant increase either in apoptosis or in the Sphase arrest.…”

Section: Discussionsupporting

confidence: 92%

“…The evidence that pre-incubation of HT-29 colon carcinoma cells with FU before SN-38 achieves synergism of action is partially in contrast with results reported by other authors, which suggest that the sequential exposure of cells to FU before IRI produces only additive activity (Mans et al, 1999). These differences may depend on the specific colon tumour cell model used.…”

Section: Discussioncontrasting

confidence: 64%

“…Indeed, the administration of IRI before FU produced additive or synergistic effects in all colon carcinoma cell lines tested (Guichard et al, 1998;Mans et al, 1999), whereas both the exposure of cells to FU before IRI and the simultaneous administration of both drugs produced antagonistic or only additive activity, depending on the colon tumour cell model (Mans et al, 1999). Similar findings were also reported in vivo, in athymic mice xenografts of colon carcinoma cells (Guichard et al, 1997).…”

supporting

confidence: 75%

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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

et al. 2006

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 64%

supporting

confidence: 75%

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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

et al. 2006

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“…It is also questionable whether 5-FU in FOLFIRI is necessary in patients who were already exposed to fluoropyrimidine. In vitro studies have shown that irinotecan downregulates thymidylate synthase expression in tumor cells, leading to synergy between irinotecan and 5-FU [26,27]. In metastatic colorectal cancer (CRC), fluoropyrimidine is usually reintroduced and combined with another drug in secondline therapy even after first-line fluoropyrimidine-based chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival

Kang

et al. 2012

Gastric Cancer

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Background The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival. Methods Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m 2 in a 2-h infusion) on day 1, and then leucovorin (200 mg/m 2 in a 2-h infusion) and 5-FU (a 400 mg/m 2 bolus, followed by 600 mg/m 2 in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m 2 in a 2-h infusion) on day 1, and then leucovorin (400 mg/m 2 in a 2-h infusion) and 5-FU (a 400 mg/m 2 bolus, followed by 2400 mg/m 2 in a 46-h continuous infusion) on day 1. Results A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS. Conclusions The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.

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“…Such cell cycle-mediated drug resistance has also been observed with other drug combinations. For example, simultaneous exposure of HT29 cells to 5-FU and irinotecan demonstrated antagonism, caused by arrest in G2 phase by irinotecan and concomitant resistance to S-phase specific 5-FU (Guichard et al, 1997;Mans et al, 1999). However, this antagonism could be overcome by sequential exposure to 5-FU followed by irinotecan after a 6 h delay (Guichard et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines

Harris¹,

Mistry²,

Freathy³

et al. 2005

Br J Cancer

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XR5944 (MLN944), a novel bis-phenazine, has demonstrated potent cytotoxic activity against a variety of murine and human tumour models. In the present study, the antitumour activity of XR5944 was investigated in combination with 5-fluorouracil (5-FU) or irinotecan in human colon carcinoma cell lines and xenografts. In vitro cytotoxicity of the combinations following exposure to the drugs sequentially or simultaneously was evaluated by the sulphorhodamine-B assay and interactions were determined using medianeffect analysis. Antagonism was observed (CI41) following exposure of HT29 cells simultaneously to XR5944 and 5-FU or SN38 (active metabolite of irinotecan). In contrast, sequential exposure of either combination in either order demonstrated at least an additive response (CIp1). At least an additive response was also observed with these combinations in HCT116 cells regardless of schedule. Antitumour activity in HT29 xenografts in nude mice was enhanced by sequential administration of 5-FU (65 mg kg À1 ) or irinotecan (CPT-11) (35 mg kg À1 ) 48 h before XR5944 (5, 10, or 15 mg kg À1 ) compared to single agent treatment at the same or higher doses. Administration of irinotecan (35 mg kg À1 ) and XR5944 (15 mg kg À1 ) just 30 min apart yielded similar efficacy to sequential administration 48 h apart. All combinations were well tolerated. These data suggest that combinations of XR5944 with irinotecan or 5-FU are of significant interest in the treatment of colon cancer.

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Sequence-dependent growth inhibition and DNA damage formation by the irinotecan–5-fluorouracil combination in human colon carcinoma cell lines

Cited by 93 publications

References 29 publications

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

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

Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival

Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines

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