Expression of DNA topoisomerase I and DNA topoisomerase II-alpha in carcinoma of the colon.

New anticancer drugs targeting DNA topoisomerase I (Topo I) are now approved for clinical use for the treatment of colon cancer. From laboratory work, it is known that tumors cells with high Topo I are sensitive to these drugs and that tumor cells with low Topo I are relatively resistant. The Topo I active drugs are also S-phase specific, indicating that cytoxicity is dependent on DNA replication and cell proliferation. To date, there is no correlation between the molecular characteristics of human colon cancers with response to Topo I active drugs. To begin to correlate biologic response to Topo I drugs with the molecular characteristics of the neoplasm, we studied Topo I and DNA topoisomerase II-alpha (Topo II-alpha) expression in 29 cases of colon cancer. With use of a new immunohistochemical stain specific for Topo I, we found elevated Topo I expression in 25 (86%) of the 29 cases. Twenty-four of the 29 cases were right-sided lesions and were previously well characterized with respect to microsatellite sequences. Topo I was elevated in 9 (82%) of 11 tumors with stable microsatellite sequences and in 11 (85%) of 13 tumors with unstable microsatellite sequences. We found no correlation between Topo I expression and Dukes' stage. A proliferation index, estimated by immunohistochemical staining for Topo II-alpha was also performed. The average Topo II-alpha index of the 29 cases studies was 63.6 (standard deviation, 14.1), indicating that colon carcinomas contain a large percent of cycling cells. There was no difference in Topo II-alpha indices between tumors with stable (average Topo II-alpha index, 61.6) or unstable microsatellite sequences (average Topo II-alpha index, 65.9).