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

Jansen, W. J. M.; Hulscher, T.M.; Ark-Otte, J. van; Giaccone, Giuseppe; Pinedo, H.M.; Boven, E.

doi:10.1038/bjc.1998.58

Cited by 53 publications

(39 citation statements)

References 23 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. Our study did not support such a role as no correlation was found between P-glycoprotein encoding gene expression (MDR1) and CPT-11 responses and, furthermore, a diversity of mdr1 gene expression (a range of 80-fold) in our series of CRCs was shown.…”

Section: Discussionmentioning

confidence: 50%

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: 50%

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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“…In selected cell lines expressing P-glycoprotein, this transporter appeared to influence the sensitivity to CPT-11 and SN-38 in vitro, but this had little influence on the activity of the drugs in xenografts (Jansen et al, 1998). Moreover, MRP expression did not appear to affect the activity of CPT-11 or SN-38.…”

Section: Discussionmentioning

confidence: 95%

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

Ark-Otte

Kedde²,

Vijgh³

et al. 1998

Br J Cancer

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Summary Irinotecan (CPT-11) is a semisynthetic camptothecin derivative with a broad spectrum of anti-tumour activity. Carboxylesterase (CE) catalyses the conversion of CPT-11 to , the active form of CPT-11. The antiproliferative effects of CPT-11 and SN-38, CE-activity and topoisomerase protein expression were investigated in five human small-cell lung cancer (SCLC) cell lines and four human non-small-cell lung cancer (NSCLC) cell lines. Antiproliferative activity, expressed as IC50 values, was determined using the MTT assay. CPT-11 was significantly more active in SCLC than in NSCLC cell lines (P = 0.0036), whereas no significant difference between histological types was observed with SN-38. A significant correlation (r2 = 0.52, P = 0.028) was observed between CE activity and chemosensitivity to CPT-11 but not to SN-38, and significantly higher CE activity was observed in SCLC compared with NSCLC cell lines (P = 0.025). Western blotting experiments showed topoisomerase protein expressions within a factor of 2, and a granular nuclear staining was detectable in all cell lines by immunocytochemistry of cytospins. No correlation was observed between protein expression and sensitivity to CPT-11 or SN-38. Cellular and medium concentrations of CPT-11 and SN-38 were measured by high-performance liquid chromatography (HPLC) in one SCLC cell line with high CE activity and high sensitivity to CPT-11, and one NSCLC cell line with low sensitivity to CPT-1i1 and CE activity. Intracellular concentrations of CPT-11 and SN-38 were higher in the SCLC cell line, and this was associated with an increase in cellular uptake of CPT-11 compared with the medium, and an increased intracellular formation of SN-38. In conclusion, CE activity appears to be associated with higher sensitivity to CPT-1i1 in human lung cancer cell lines and may partly explain the difference in the in vitro sensitivity to CPT-11 between SCLC and NSCLC cells. The assessment of CE activity in clinical material of lung cancer patients undergoing treatment with CPT-11 may be warranted. However, other mechanisms may influence sensitivity to CPT-11, possibly including drug transport.

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“…Expression of ABC transporters is associated with resistance to SN-38 in several malignant cell lines (36). In addition, the ABCC1 pump has higher affinity to SN-38 than any other Figure 4.…”

Section: Discussionmentioning

confidence: 99%

Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

Azrak¹,

Pendyala

et al. 2005

Molecular Cancer Therapeutics

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The combination of methylselenocysteine and irinotecan (CPT-11) is synergistic against FaDu and A253 xenografts. Methylselenocysteine/CPT-11 increased tumor cure rate to 100% in FaDu and to 60% in A253. In this study, the effect of methylselenocysteine on pharmacokinetic and pharmacogenetic profiles of genes relevant to CPT-11 metabolic pathway was evaluated to identify possible mechanisms associated with the observed combinational synergy. Nude mice bearing tumors (FaDu and A253) were treated with methylselenocysteine, CPT-11, and a combination of methylselenocysteine/CPT-11. Samples were collected and analyzed for plasma and intratumor concentration of CPT-11 and 7-ethyl-10-hydroxyl-camptothecin (SN-38) by high-performance liquid chromatography. The intratumor relative expression of genes related to the CPT-11 metabolic pathway was measured by real-time PCR. After methylselenocysteine treatment, the intratumor area under the concentration-time curve of SN-38 increased to a significantly higher level in A253 than in FaDu and was associated with increased expression of CES1 in both tumors. Methylselenocysteine/CPT-11 treatment, compared with CPT-11 alone, resulted in a significant decrease in levels of ABCC1 and DRG1 in FaDu tumors and an increase in levels of CYP3A5 and TNFSF6 in A253 tumors. No statistically significant changes induced by methylselenocysteine/CPT-11 were observed in the levels of other investigated variables. In conclusion, the significant increase in the cure rate after methylselenocysteine/CPT-11 could be related to increased drug delivery into both tumors (CES1), reduced resistance to SN-38 (ABCC1 and DRG1) in FaDu, and induced Fas ligand apoptosis (TNFSF6) in A253. No correlation was observed between cure rate and other investigated variables (transporters, degradation enzymes, DNA repair, and cell survival/death genes) in either tumor. [Mol Cancer Ther 2005;4(5):843 -54]

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

Cited by 53 publications

References 23 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

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

Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

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