Determinants of CPT-11 and SN-38 activities in human lung cancer cells

Ark-Otte, J. van; Kedde, Martijn; Vijgh, W.J.F. van der; Dingemans, Anne Marie C.; Jansen, W. J. M.; Pinedo, H.M.; Boven, E.; Giaccone, Giuseppe

doi:10.1038/bjc.1998.362

Cited by 76 publications

(61 citation statements)

References 21 publications

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“…These differences were not due to different levels of top1, as evaluated by a semiquantitative method (Murphy et al, 1990), as already published (Goldwasser et al, 1995;van Ark-Otte et al, 1998). Jansen et al (1998) proposes a role for P-glycoprotein (encoded by mdr1 gene) in lack of efficacy of numerous compounds, including CPT-11.…”

Section: Discussionmentioning

confidence: 55%

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Bras-Gonçalves

Rosty²,

Laurent‐Puig³

et al. 2000

Br J Cancer

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Summary Biological parameters influencing the response of human colorectal cancers (CRCs) to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability phenotype (MSI + when altered). Five CRC xenografts were established from clinical samples. All five had a functional p53, two were MSI + and three were MSI -. Tumour-bearing nude mice were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg -1 of CPT-11, four injections at 4-day intervals, four of the five xenografts responded to CPT-11 (growth delay of up to 10 days); the non-responder tumour was MSI -. At 40 mg kg -1 of CPT-11, six injections at 4-day intervals, the five CRCs displayed variable but marked responses with complete regressions. In order to assess the role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line was MSI -/Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI + /wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transfection. LoVo tumours (MSI + /mutp53) were more sensitive than X17LoVo (MSI + /mutp53. HT 29 tumours (MSI -Imutp53), were refractory to CPT-11 while HT29A3 tumours (MSI -/wtp53) were sensitive, showing that wtp53 improves the drugresponse in these MSI -tumours. Levels of mRNA expression of top1, fasR, TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken together, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI phenotype moderately influences the CPT-11 sensitivity, MSI + being more sensitive than MSI -CRC freshly obtained from patients, mutp53 status being associated with a poor response to CPT-11. © 2000 Cancer Research Campaign Keywords: CPT-11; MSI; p53; top1; human colorectal cancer; nude mice (2000) 82(4), 913-923 © 2000 Cancer Research Campaign DOI: 10.1054/ bjoc.1999.1019, available online at http://www.idealibrary.com on et al, 1998). Cells with functional wtp53 are found to be dramatically more sensitive to many of the commonly used anticancer agents (Fujiwara et al, 1994;Lowe et al, 1993Lowe et al, , 1994McDonald and Brown 1998). In MSI + tumours, defects in mismatch repair genes could lead to the accumulation of unrepaired or misrepaired DNA during DNA replication, rendering them more sensitive for CPT-11 effect.Other resistance mechanisms to CPT-11 could also be implicated. Overexpression of the multidrug resistance gene product, P-glycoprotein, encoded by the mdr1 gene has been incriminated in tumour cell resistance to numerous compounds (Gottesman et al, 1996). Its role in the lack of sensitivity of tumour cells to CPT-11 has been described . Two groups have recently shown that colorectal cancers of the colonic mucosa express the fas receptor (fasR), a cell membrane determinant which triggers the apoptotic casc...

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Section: Discussionmentioning

confidence: 55%

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Bras-Gonçalves

Rosty²,

Laurent‐Puig³

et al. 2000

Br J Cancer

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“…A clear relationship between carboxylesterase level and the chemosensitivity of human small-cell and nonsmall-cell lung cancer cell lines has been demonstrated in vitro, where irinotecan resistance was encountered in cell lines with low carboxylesterase expression. 30 Furthermore irinotecan inhibits topoisomerase I -unlike doxorubicin and mitoxantrone which iact on topoisomerase II. Topoisormase I expression has been described to be proportional to irinotecan cytotoxic effects in yeast systems and mammalian cell lines.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin and mitoxantrone drug eluting beads for the treatment of experimental peritoneal carcinomatosis in colorectal cancer

Keese

Gasimova

Schwenke

et al. 2009

Intl Journal of Cancer

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We investigated the therapeutic efficiency of sulfonate-modified polyvinyl alcohol beads loaded with doxorubicin, irinotecan or mitoxantrone in vitro and in vivo in a model of experimental peritoneal carcinomatosis (PC). In vitro, cell proliferation was efficiently impaired by doxorubicin drug eluting bead (DEB) treatment while mitoxantrone DEBs were less effective than. Irinotecan showed little effect for both DEBs and free drug. Apoptosis was not different between free mitoxantrone and the DEB form while more apoptosis induction was observed in cells incubated with free doxorubicin and irinotecan. Experimental PC was produced in mice. The therapeutic efficiency of either mitoxantrone and doxorubicin DEB or free drugs were compared. Mice were treated either once on day 12 or by 3 repetitive applications on days 7, 10 and 12. Mice treated by DEBs showed less weight loss and mortality. Therapeutic effect was determined by measuring tumor volume and tumor load on the day 15 after tumor inoculation. For the single application on the day 12, an advantage could be observed for the free drugs. After 3 repeated injections of both free and mitoxantrone DEB no difference in tumor load or tumor volume could be observed. Least tumor load and tumor volume was observed in mice that received 3 repeated injections of doxorubicin DEB. No animal survived 3 injections of free doxorubicin. We conclude that bead encapsulation of chemotherapeutic drugs may show the advantage of less toxicity in peritoneal spread of colorectal cancer. '

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“…24 Briefly, exponentially growing cells were lysed in 20 mM cold Tris-HCl, pH 7.5, by sonication. The lysates were then centrifuged at 15,000g for 30 min at 4°C.…”

Section: Determination Of Carboxylesterase Activitymentioning

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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Determinants of CPT-11 and SN-38 activities in human lung cancer cells

Cited by 76 publications

References 21 publications

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Doxorubicin and mitoxantrone drug eluting beads for the treatment of experimental peritoneal carcinomatosis in colorectal cancer

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

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