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Intrinsic chemotherapy resistance to the tubulin‐binding antimitotic agents in renal cell carcinoma
Author(s) -
Ferguson Roisean E.,
Jackson Sharon M.,
Stanley Anthea J.,
Joyce Adrian D.,
Harnden Patricia,
Morrison Ewan E.,
Patel Poulam M.,
Phillips Roger M.,
Selby Peter J.,
Banks Rosamonde E.
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20816
Subject(s) - vinblastine , paclitaxel , vincristine , in vivo , cancer research , downregulation and upregulation , multidrug resistance associated protein 2 , cell culture , chemotherapy , p glycoprotein , medicine , cancer , drug resistance , biology , multiple drug resistance , cyclophosphamide , biochemistry , atp binding cassette transporter , transporter , genetics , microbiology and biotechnology , gene
Renal cancer is one of the most chemoresistant tumor types. Using a panel of 10 established renal cancer cell lines that have not been subjected to prior drug selection, the range of functional resistance phenotypes to the tubulin‐binding agents paclitaxel, vinblastine, vincristine and patupilone (epothilone B, EPO906) was determined, together with expression of P‐glycoprotein (PgP), multidrug resistance associated protein‐2 (MRP2) and major vault protein (MVP) proteins. The IC 50 values for vincristine correlated positively with PgP expression (r = 0.73; p = 0.031), with values for paclitaxel and vinblastine just failing to reach significance. A significant positive correlation was observed for sensitivity to paclitaxel and MRP2 expression only (r = 0.8; p = 0.013). MVP expression did not correlate with sensitivity to any of the drugs examined. All cell lines exhibited much greater sensitivity to patupilone, demonstrating for the first time the potential use of patupilone in this cancer. In tissue samples from chemotherapy‐naive renal cell carcinoma (RCC) patients, marked downregulation or absence of PgP in many tumor cells with expression levels more similar to sensitive cell lines rather than the resistant lines was seen. Similarly, MRP2 was absent or only weakly present in tumor cells, whereas MVP was very strongly upregulated in most tumor samples. This study illustrating discrepancies between results exclusively based on studies in cell lines and findings in vivo suggests that the role of PgP and MRP2 in intrinsic resistance in RCC in vivo may be less than expected from the in vitro findings and supports a potential role for MVP on the basis of in vivo expression studies. © 2004 Wiley‐Liss, Inc.