CPT‐11 in human colon‐cancer cell lines and xenografts: Characterization of cellular sensitivity determinants

Jansen, W. J. M.; Zwart, Bas; Hulscher, Saskia; Giaccone, Giuseppe; Pinedo, H.M.; Boven, E.

doi:10.1002/(sici)1097-0215(19970127)70:3<335::aid-ijc15>3.3.co;2-b

Cited by 16 publications

(26 citation statements)

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“…In the panel of five unselected human colon cancer cell lines, we have indeed found a positive correlation between the DNA topoisomerase I activity and the sensitivity to carboxylesterase-activated CPT-l1 and to SN-38 (Jansen et al, 1997a). Goldwasser et al (1995) have demonstrated a positive correlation between camptothecin sensitivity and the amount of drug-stabilized cleavable complexes.…”

Section: Discussionsupporting

confidence: 63%

“…In a previous study in five unselected human colon cancer cell lines, we also demonstrated a difference in efficacy between carboxylesterase-activated CPT-11 and SN-38 (Jansen et al, 1997a). Explanations may be that various nutrients in tissue culture medium might inhibit the activation of the enzyme or that the carboxylesterase extract from porcine liver is not a good substitute for the endogenous carboxylesterase converting CPT-11 in other species.…”

Section: Discussionmentioning

confidence: 54%

“…In this respect, Niwa et al (1995) have found a correlation between topoisomerase I mRNA and the sensitivity to CPT-11 in various human cancer cell lines, which displayed natural differences in sensitivity to CPT-1 1. Our group (Jansen et al, 1997a) as well as the group of Goldwasser et al (1995) have demonstrated that there was no relation between topoisomerase I mRNA expression and sensitivity to camptothecins. In the present study, the extent of topoisomerase I mRNA expression was similar in the multidrug-resistant sublines and the parental cell lines, which did not reflect the differences in sensitivity to CPT-1 1 and SN-38.…”

Section: Discussionmentioning

confidence: 61%

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CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Jansen

Hulscher²,

Ark-Otte³

et al. 1998

Br J Cancer

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Summary The relevance of P170-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) for the sensitivity to CPT-11 was investigated in human malignant cell lines as well as in human tumour xenografts. In vitro, the P-gp-positive sublines BRO/mdrl.1 (transfected with MDR1) and 2780AD were slightly cross-resistant against carboxylesterase-activated CPT-11. Cross-resistance against SN-38 was present in 2780AD cells, but not in BRO/mdrl.1 cells. The P-gp modulators BIBW22BS, verapamil and dexniguldipine partly reversed the resistance against CPT-11 in the P-gp-positive sublines. BIBW22BS was the most effective modulator in the reversal of the resistance against carboxylesterase-activated CPT-11 as well as against in the 2780AD subline. In contrast to doxorubicin and vincristine, the BRO/mdrl.1 xenografts were at least as sensitive to CPT-11 as the BRO xenografts. The 2780AD xenografts were slightly less sensitive than the parent tumours, but there was no difference in topoisomerase I DNA unwinding activity. Therefore, the high retention of the multidrugresistant phenotype of 2780AD cells in vivo may be the cause of the low cross-resistance against CPT-11. The MRP-positive subline GLC4/ADR was cross-resistant against carboxylesterase-activated CPT-11 and SN-38. GLC4/ADR cells, however, demonstrated a twofold lower topoisomerase I activity than GLC4 cells. Cross-resistance against the camptothecin derivatives was not apparent in the MRPtransfected subline of SW1573/Si. In conclusion, P-gp-positive cells show a low cross-resistance against CPT-11/SN38, which is only apparent with high P-gp expression in vivo. MRP does not seem to play a role in the sensitivity to

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 61%

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CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Jansen

Hulscher²,

Ark-Otte³

et al. 1998

Br J Cancer

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“…[14][15][16][17] Other studies determining predictive markers of CPT-11 efficacy have been highly controversial. [18][19][20][21][22] In vitro studies in colon cancer cell lines have suggested that Topo I activity may be a potential determinant of CPT-11 sensitivity. 18,19 Saltz et al described a significant correlation between mRNA levels of Topo I and response to CPT-11 based treatment in a small group of patients with metastatic CRC.…”

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confidence: 99%

Molecular determinants of irinotecan efficacy

Vallböhmer

Iqbal

Yang

et al. 2006

Intl Journal of Cancer

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Molecular markers predicting the efficacy of CPT‐11 based chemotherapies in patients with colorectal cancer (CRC) are unknown. Therefore, we investigated whether mRNA levels of drug targets (Topoisomerase I, TS), enzymes involved in 5‐FU metabolism (DPD), in angiogenesis (EGFR, IL‐8, VEGF) and in DNA‐repair/drug detoxification (ERCC1, GST‐P1) are associated with the clinical outcome of patients with CRC treated with first‐line CPT‐11 based chemotherapy. Thirty three patients with metastatic CRC were included in the study. Intratumoral gene expression levels were assessed from paraffin‐embedded tissue samples, using laser capture microdissection and quantitative Real‐Time PCR. Complete response was observed in 1 patient, partial response in 12 patients, stable disease in 13 patients and progressive disease in 6 patients. Response was inevaluable for 1 patient. Patients with complete response or partial response were classified as responders, while patients with stable disease or progressive disease were classified as nonresponders. High intratumoral mRNA levels of EGFR, ERCC1 and GSPT‐P1 were each significantly associated with response to CPT‐11 based chemotherapy. Recursive partitioning analysis showed that mRNA levels of EGFR and ERCC1 are primarily responsible for delineating responders from nonresponders. Also, the combination of high intratumoral gene expression levels of both EGFR and ERCC1 was significantly associated with progression‐free survival. The mRNA levels of EGFR had a significant correlation with expression levels of ERCC1, GST‐P1 and VEGF. This small retrospective study suggests that gene expression levels of EGFR, ERCC1 and GST‐P1 may be useful in predicting the clinical outcome of patients with metastatic CRC treated with first‐line CPT‐11 based chemotherapy. © 2006 Wiley‐Liss, Inc.

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“…The collision of CPT-11-stabilized topo I-bridged DNA breaks, referred to as cleavable complexes, with moving replication forks leads to lasting single-strand breaks and to cell death. Since the activity of topo I is frequently higher in colorectal tumors than in the normal colonic tissue, it may confer tumor specificity of the CPT-11-mediated effects, 6 and a decrease of topo I activity may contribute to the resistance of tumor cells. 7 The response in vivo appears also to correspond to the amount of cleavable complexes.…”

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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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CPT‐11 in human colon‐cancer cell lines and xenografts: Characterization of cellular sensitivity determinants

Cited by 16 publications

References 0 publications

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Molecular determinants of irinotecan efficacy

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

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