Non‐P‐glycoprotein‐mediated Atypical Multidrug Resistance in a Human Bladder Cancer Cell Line

• Published in: Cancer science 1995-11, Vol.86 (11), p.1112-1118
• Main Authors: Naito, Seiji, Hasegawa, Shuji, Yokomizo, Akira, Koga, Hirofumi, Kotoh, Shuji, Kuwano, Michihiko, Kumazawa, Joichi
• Format: Article
• Language: English
• Subjects: Adriamycin; Alkaloids; Antineoplastic agents; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - biosynthesis; ATP-Binding Cassette Transporters - biosynthesis; Biological and medical sciences; Bladder cancer; Cancer; Carcinoma, Transitional Cell - metabolism; Carcinoma, Transitional Cell - pathology; Chemotherapy; Cisplatin - pharmacology; Deoxyribonucleic acid; DNA; DNA topoisomerase; DNA topoisomerase (ATP-hydrolysing); DNA topoisomerase II; DNA Topoisomerases, Type II - biosynthesis; DNA Topoisomerases, Type II - deficiency; Doxorubicin - metabolism; Doxorubicin - pharmacology; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epirubicin - pharmacology; Etoposide; Etoposide - pharmacology; Flow cytometry; Fluorouracil - pharmacology; General aspects; Glycoproteins; Humans; MDR1 protein; Medical sciences; Mitomycin - pharmacology; mRNA; MRP protein; Multidrug resistance; Multidrug Resistance-Associated Proteins; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; P-Glycoprotein; Pharmacology. Drug treatments; Phenotypes; Selection, Genetic; Topoisomerase II Inhibitors; Tumor Cells, Cultured - drug effects; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Verapamil - pharmacology; Vinca Alkaloids - pharmacology
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.1995.tb03028.x

A human bladder cancer cell line resistant to adriamycin (ADM), T24/ADM9 has been established in vitro by exposing T24 parent cells to progressively higher concentrations of the drug over a period of 12 months. The T24/ADM9 cells were found to be 9 times more resistant to ADM than the T24 parent, and showed various degrees of cross‐resistance to an ADM derivative, vinca alkaloids and a DNA topoisomerase II (Topo ID‐targeting agent, etoposide. No significant difference was observed in the cellular accumulation of ADM between the T24/ADM9 and T24 parent cells. A Northern blot analysis showed an overexpression of multidrug resistance‐associated protein (MRP) mRNA, but no overexpression of multidrug resistance‐1 (MDR1) mRNA was observed in the T24/ADM9 cells. A flow cytometric analysis showed that the MDR1 gene product, P‐glycoprotein (Pgp), is not expressed on the T24/ADM9 cells. T24/ADM9 showed approximately the parental level of DNA Topo II catalytic activity. In Western blot and Northern blot analyses, however, the cellular level of DNA topo II was apparently much lower in T24/ADM9 than in the T24 parent. Thus, these results suggest that a decreased cellular level of DNA Topo II and an overexpression of MRP gene may be responsible for the expression of an MDR phenotype in the T24/ADM9 cells and that such non‐Pgp‐mediated, atypical MDR may develop in bladder cancer treated with chemotherapy including ADM.