Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma.
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.
Ferguson
Roisean E
RE
Cancer Research U.K. Clinical Centre, St. James's University Hospital, Leeds, United Kingdom.
Jackson
Sharon M
SM
Stanley
Anthea J
AJ
Joyce
Adrian D
AD
Harnden
Patricia
P
Morrison
Ewan E
EE
Patel
Poulam M
PM
Phillips
Roger M
RM
Selby
Peter J
PJ
Banks
Rosamonde E
RE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000737:chemistry; D010641:Phenotype; D012680:Sensitivity and Specificity; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry*; D015854:Up-Regulation; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin; D014747:Vinblastine; D014750:Vincristine; C000715087:ABCC2 protein, human; C022616:thiazolyl blue