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Relationship between Topoisomerase II Level and Chemosensitivity in Human Tumor Cell Lines¹

Imperial Cancer Research Fund, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU [A. M. F., S. M. D., A. L. H., I. D. H.]; Department of Oncology, University College and Middlesex School of Medicine, London W1P 8BT [C. M. C., J. A. H.]; and Department of Pathology, St. Paul's Hospital, London WC2H 9AE [M. C. W., J. R. W. M.], United Kingdom

Patients with metastatic testis tumors are generally curable using chemotherapy, whereas those with disseminated bladder carcinomas are not. We have compared levels of the nuclear enzyme topoisomerase II in three testis (SuSa, 833K, and GH) and three bladder (RT4, RT112, and HT1376) cancer cell lines which differ in their sensitivity to chemotherapeutic agents. The testis cell lines were more sensitive than the bladder lines to three drugs whose cytotoxicity is mediated in part by inhibiting topoisomerase II: amsacrine; Adriamycin; and etoposide (VP16). The frequency of DNA strand breaks induced by amsacrine was higher (1.5- to 13-fold) in the testis cells than in the bladder cells. The level of topoisomerase II-mediated DNA strand breakage in vitro, measured by filter trapping of amsacrine-induced protein:DNA cross-links, was similarly higher in nuclear extracts from the testis than the bladder cells. Western blot analysis showed a generally higher level of topoisomerase II protein in testis than in bladder cell nuclear extracts. Topoisomerase II protein expression broadly correlated with drug-induced strand breakage in both protein extracts and whole cells, but not with population doubling time. However, despite a 2- to 20-fold increased sensitivity to the different topoisomerase II inhibitors, the testis line 833K had a less than 2-fold higher level of topoisomerase II protein than that of the bladder line RT4. These results indicate that the level of expression of topoisomerase II is an important determinant of the relative chemosensitivity of testis and bladder tumor cell lines, but that additional factors must contribute to the extreme chemosensitivity of testis cells.

¹ Supported by the Imperial Cancer Research Fund, the Cancer Research Campaign, and the N. E. Thames Regional Health Authority.

² To whom requests for reprints should be addressed.

Received 6/25/91. Accepted 10/ 2/91.

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