New drugs in colorectal cancer: A review of antitumor activity and cross-resistance patterns of topoisomerase I inhibitors, thymidylate synthetase inhibitors, and oxaliplatin

For almost three decades, 5-fluorouracil has been the only active agent with a documented objective response rate over 10% in colorectal carcinoma. However, recently a number of new classes of antineoplastic agents have entered the clinic, and several of them appear to have activity in colorectal carcinoma. Based on biochemical considerations, specific inhibitors of thymidylate synthetase, namely tomudex (ZD1694), LY231514 and AG337, have been developed which fit into the folate binding domain of the enzyme. Two of these, tomudex and LY231514, have demonstrated activity in colon cancer in the range which can be expected for fluoropyrimidines. Furthermore, preclinical data indicate that specific thymidylate synthetase inhibitors and fluoropyrimidines display incomplete cross resistance. Especially cells with acquired resistance to these folate-based thymidylate synthetase inhibitors were, in their majority, still sensitive to 5-fluorouracil. Topoisomerase I inhibitors possess a novel mechanism of cytotoxic action and appear to be active in a variety of tumors. 9-aminocamptothecin and topotecan have demonstrated only limited activity in the initial trials in colorectal cancer. However, irinotecan has been extensively studied. Irinotecan is active in first-line treatment with an overall response rate of 22% and, more important, shows also considerable antitumor efficacy in pretreated patients. A response rate of 16% was demonstrated for patients with documented progression on a 5-fluorouracil/folinic acid regimen, making irinotecan the most active single agent for second-line therapy of colon cancer. Finally, oxaliplatin, a diaminocyclohexane-platinum(II) complex introduced into the clinic several years ago, could play an important role in colon cancer. The drug shows single-agent activity in first-and second-line treatment (23% and 10% objective responses, respectively). However, the most important feature of oxaliplatin appears to be its property to act synergistically with 5-fluorouracil. It has been demonstrated that approximately 25% of patients will respond if oxaliplatin is added to the same 5-fluorouracil regimen, once patients develop resistance to 5-fluorouracil. Taken together, the introduction of these new drugs has clearly increased our therapeutic options in colorectal carcinoma. All of them have single-agent activity and appear to be not cross-resistant. The task of the future will be to clearly define their exact role in the overall treatment strategy of metastatic as well as locally advanced colorectal carcinoma.