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Cellular resistance to mitomycin C is associated with overexpression of MDR‐1 in a urothelial cancer cell line (MGH‐U1)
Author(s) -
Hayes M.C.,
Birch B.R.,
Cooper A.J.,
Primrose J.N.
Publication year - 2001
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1046/j.1464-410x.2001.02027.x
Subject(s) - mitomycin c , epirubicin , multiple drug resistance , cytotoxicity , abcc1 , cancer research , biology , bladder cancer , clone (java method) , drug resistance , microbiology and biotechnology , chemotherapy , pharmacology , cancer , gene , in vitro , atp binding cassette transporter , cyclophosphamide , biochemistry , genetics , transporter
Objective To compare multidrug resistance (MDR)‐1 and MDR‐3 gene expression in a new urothelial cancer cell line (MGHU‐1, with resistance to mitomycin C) against controls and the established (epirubicin‐resistant) MDR clone, and to correlate MDR with cytotoxicity data. Materials and methods Resistance to mitomycin C was induced by the long‐term exposure of wild‐type MGHU‐1 cells to increasing concentrations (20–400 nmol/L) of mitomycin C. The cytotoxicity of mitomycin C or epirubicin was then compared in MGHU‐1, MGHU‐MMC (mitomycin C‐resistant) and MGHU‐1R (established MDR) cells, using the tetrazolium biomass assay. The expression of MDR‐1 and ‐3 was investigated by the reverse transcriptase‐polymerase chain reaction, using cDNA‐specific primers after titration, and compared with DNA and negative controls. Results MDR‐1 and ‐3 were significantly and equally overexpressed in MGHU‐1R, and associated with a dramatic increase in the 50% inhibitory drug concentration ( P < 0.001) for mitomycin C and epirubicin against controls. In MGHU‐MMC, the overexpression of MDR‐1 was three times greater than that of MDR‐3. The cytotoxicity profile for both agents was very similar to that of MGHU‐1R. Trace amounts of MDR‐1, but not MDR‐3, were identified in the MGHU‐1 wild‐type. Conclusions Urothelial cancer cell resistance to mitomycin C is associated with cross‐resistance to epirubicin and overexpression of MDR‐1, suggesting that mitomycin C falls within the MDR category. Clinical application of this methodology may allow patients to be identified who are unlikely to benefit from intravesical chemotherapy.