Combination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity

Pavillard, Valérie; Formento, Patricia; Rostagno, Philippe; Formento, Jean–Louis; Fischel, Jean‐Louis; Francoual, M; Etienne, Marie‐Christine; Milano, Gérard

doi:10.1016/s0006-2952(98)00205-6

Cited by 61 publications

(43 citation statements)

References 15 publications

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“…This observation differs from previous results showing synergism when applying SN38 before FUFA (Pavillard et al, 1998). A reason for this discrepency may lie in the different tested schedules, SN38-FUFA combination having been previously tested as two 48 h consecutive sequence for each drug, whereas in the present study a 24 h sequence was applied for SN38 and a 48 h sequence for FU.…”

Section: Discussioncontrasting

confidence: 94%

“…Moreover, additional cytometry analyses performed in the present study demonstrated that SN38 significantly induced cell recruitment in the S-G2-M phases 24 h and 48 h after SN38 exposure (unshown data). Also, the impact of camptothecins on the cell cycle was previously reported by others (Goldwasser et al, 1996) and ourselves (Pavillard et al, 1998). Since FU acts preferentially on cells entering the S phase, all together these data indicate that the SN38 position significantly influences the cytotoxicity of FUFA: in schedule A, FU was applied 26 h after the end of SN38 exposure, at the time of S phase recruitment, thus leading to greater FU cytotoxic effects as compared to schedule B.…”

Section: Discussionsupporting

confidence: 76%

“…More recently, it has been shown that the CPT11-FUFA combination produced a higher response rate (Douillard et al, 2000;Saltz et al, 2000) and prolonged survival (Douillard et al, 2000) in comparison to FUFA in advanced colorectal cancer patients. As for the LOHP-FUFA association, these clinical results are in agreement with preclinical data showing synergistic interactions between CPT11 and FUFA (Guichard et al, 2000;Pavillard et al, 1998).…”

supporting

confidence: 86%

“…24 h later, cells were exposed to the drugs. We previously established that an optimal interaction was obtained between SN38 and FUFA when SN38 was applied before FUFA (Pavillard et al, 1998). In complement to these previously published data we made preliminary experiments so as to select the drug sequence to be definitively tested in the present study.…”

Section: Evaluation Of Cytotoxicitymentioning

confidence: 90%

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Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

et al. 2001

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Summary A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)-fluorouracil (FU)-folinic acid (FA) combination and by CPT11-FU-FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU-FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC 50 ) of the double association without that drug divided by the IC 50 of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU-FA.

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Section: Discussioncontrasting

confidence: 94%

Section: Discussionsupporting

confidence: 76%

supporting

confidence: 86%

Section: Evaluation Of Cytotoxicitymentioning

confidence: 90%

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Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

et al. 2001

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“…11,12 Treatment of lung cancer, 25 colon carcinoma 26 and ovarian carcinoma cells 12 or fibroblasts 11 with CPT-11 or SN-38 was previously shown to induce G2/M arrest. Previous studies also indicated that p53 and p21 proteins are essential for the sustaining of but not for triggering of the G2/M arrest after DNA damage induced by ionizing radiation or temozolomide treatment.…”

Section: Discussionmentioning

confidence: 99%

Cellular effects of CPT‐11 on colon carcinoma cells: Dependence on p53 and hMLH1 status

Magrini¹,

Bhonde²,

Hanski³

et al. 2002

Intl Journal of Cancer

112

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Irinotecan (CPT-11), a recently introduced component of a standard chemotherapy for colorectal cancer, induces in colon cancer cell lines in vitro cell cycle arrest and apoptosis. Since sporadic colon carcinomas exhibit in 50 -60% mutations in the p53 gene and in 10 -15% an MSI phenotype due in the great majority of the cases to hMLH1 inactivation, we investigated how these lesions influence the cellular effects of CPT-11 by using colorectal carcinoma cell line HCT116 (which has the genotype p53 ؉/؉ ,hMLH1 -) and 2 derivative cell lines with the genotypes p53 ؉/؉ ,hMLH1 ؉ and p53 -/-,hMLH1 -. CPT-11 treatment induced G2/M arrest in all 3 cell lines within 48 hr. In the p53 ؉/؉ ,hMLH1 ؉ cell line, G2/M arrest was maintained for at least 12 days. There was little concomitant apoptosis, but this was enhanced when the hMLH1 protein was absent. This enhanced apoptosis was accompanied by a shorter duration of the G2/M arrest than in the hMLH1 ؉ cell line. Partial abrogation of G2/M arrest by caffeine enhanced apoptosis in both hMLH1 ؉ and hMLH1 -cells. By contrast, in the p53 -/-cell line, the G2/M arrest was terminated within 4 days. Termination of the G2/M arrest was accompanied by a high level of apoptosis detectable through poly(ADP-ribose)polymerase (PARP) cleavage, DNA fragmentation and by the appearance of cells with a DNA content <2N. The triggering of G2/M arrest was accompanied in the 3 cell lines by a transient phosphorylation of cdc-2, while the maintenance of the arrest in the p53 ؉/؉ cell lines was accompanied by the overexpression of p53 and p21 proteins and, consequently, by the inhibition of cdc-2 kinase activity. These data indicate that: (i) CPT-11 induces long-term arrest in p53 ؉/؉ cells and a short-term arrest followed by apoptosis in p53 -/-cells; (ii) triggering of the arrest is p53 independent and is associated with a brief increase of phosphorylation of cdc-2, while the p53-dependent maintenance of G2/M arrest is associated with the inhibition of cdc-2 kinase activity by p21; and (iii) lack of hMLH1 protein enhances CPT-11-induced apoptosis. These results may be useful for designing rational therapies dependent on the p53 and mismatch-repair status in the tumor.

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Clinical use of topoisomerase I inhibitors in anticancer treatment

Rodríguez‐Galindo

Radomski

Stewart

et al. 2000

Med. Pediatr. Oncol.

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The camptothecin analogs topotecan and irinotecan have shown to be among the most effective anticancer agents and, as S-phase specific agents, their antitumor effect is maximized when they are administered in protracted schedules. The documented activity as single agents in many adult and pediatric malignancies has been followed by their use in combination with other anticancer agents. These studies have shown promising results, and have placed topotecan and irinotecan in the first line treatment for some malignancies. However, studies to better determine the optimal schedules and sequence of combinations are needed.

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Combination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity

Cited by 61 publications

References 15 publications

Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

Cellular effects of CPT‐11 on colon carcinoma cells: Dependence on p53 and hMLH1 status

Clinical use of topoisomerase I inhibitors in anticancer treatment

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