Elevations of DNA topoisomerase I in transitional cell carcinoma of the urinary bladder: Correlation with DNA topoisomerase II-alpha and p53 expression

Abstract

DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of antitumor drugs. Laboratory studies have indicated that cells sensitive to these drugs contain elevated levels of topo I. In this study, we immunostained 49 cases of transitional cell carcinoma from the urinary bladder with a monoclonal antibody directed against human topo I. We found elevated expression of the enzyme in 77% (38 of 49). This included three of six grade 1 tumors (50%), 9 of 15 grade II tumors (60%), 14 of 15 grade III tumors (93%) and 12 of 13 grade IV tumors (92%). Because the number of cycling cells in a tumor also may be an important determinant of topo I drug response, a proliferation index (topo II-alpha) also was performed for each case. The average topo II-alpha index of grade I tumors was 7.5 × 3.8; for grade II tumors, 20.1 ± 10.5; for grade III tumors, 40.3 × 8.2; and for grade IV tumors, 50.5 ± 13.0. Because a functional p53 tumor suppressor gene may be necessary for anticancer drug response, we also evaluated our cases for alteration in p53 function. Mutations in the p53 tumor suppressor gene, estimated by immunohistochemical staining, were common, occurring in 23 of 49 cases (47%). The number of cases with elevated topo I, a large growth fraction, and a functional p53 tumor suppressor gene was 4 of 49 (8%). Our results suggest that a small population of patients with transitional cell carcinoma of the urinary bladder may have tumors with molecular features suggesting responsiveness to the new anticancer drugs targeting topo I.