Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma

Roisean E. Ferguson, Sharon M. Jackson, Anthea J. Stanley, Adrian D. Joyce, Patricia Harnden, Ewan E. Morrison, Poulam M. Patel, Roger M. Phillips, Peter J. Selby, Rosamonde E. Banks

Research output: Contribution to journalArticle

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Abstract

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 IC50 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.

LanguageEnglish
Pages155-163
Number of pages9
JournalInternational Journal of Cancer
Volume115
Issue number1
Early online date11 Jan 2005
DOIs
Publication statusPublished - 20 May 2005
Externally publishedYes

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Antimitotic Agents
Tubulin
Renal Cell Carcinoma
P-Glycoprotein
Drug Therapy
Paclitaxel
Cell Line
Vinblastine
Kidney Neoplasms
Vincristine
Neoplasms
Pharmaceutical Preparations
Inhibitory Concentration 50
Down-Regulation
epothilone B
Phenotype
major vault protein
multidrug resistance-associated protein 2
Proteins

Cite this

Ferguson, R. E., Jackson, S. M., Stanley, A. J., Joyce, A. D., Harnden, P., Morrison, E. E., ... Banks, R. E. (2005). Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma. International Journal of Cancer, 115(1), 155-163. https://doi.org/10.1002/ijc.20816
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. / Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma. In: International Journal of Cancer. 2005 ; Vol. 115, No. 1. pp. 155-163.
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Ferguson, RE, Jackson, SM, Stanley, AJ, Joyce, AD, Harnden, P, Morrison, EE, Patel, PM, Phillips, RM, Selby, PJ & Banks, RE 2005, 'Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma', International Journal of Cancer, vol. 115, no. 1, pp. 155-163. https://doi.org/10.1002/ijc.20816

Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma. / 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.

In: International Journal of Cancer, Vol. 115, No. 1, 20.05.2005, p. 155-163.

Research output: Contribution to journalArticle

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T1 - Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma

AU - Ferguson, Roisean E.

AU - Jackson, Sharon M.

AU - Stanley, Anthea J.

AU - Joyce, Adrian D.

AU - Harnden, Patricia

AU - Morrison, Ewan E.

AU - Patel, Poulam M.

AU - Phillips, Roger M.

AU - Selby, Peter J.

AU - Banks, Rosamonde E.

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N2 - 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 IC50 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.

AB - 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 IC50 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.

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KW - P-glycoprotein

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Ferguson RE, Jackson SM, Stanley AJ, Joyce AD, Harnden P, Morrison EE et al. Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma. International Journal of Cancer. 2005 May 20;115(1):155-163. https://doi.org/10.1002/ijc.20816