Chemotherapy of human colon cancer xenografts in athymic nude mice.

Abstract

The lack of effective chemotherapy in advanced colon cancer and difficulties in evaluating response in clinical trials indicate a need for experimental models to screen new agents for activity against this specific type of cancer. Xenografts of human colon cancer in nude mice reproduce many features of the original tumor specimen and could be expected to predict drug response for colon cancer with more specificity than previously used screens. NIH-Swiss nude mice bearing subcutaneous (s.c.) trocar implants of tumor tissue were used in these studies. Three serially transplantable lines of human colon cancer (designated “HT”, “CA”, and “BE”), which range in their degree of differentiation from well-differentiated adenocarcinoma to undifferentiated carcinoma, were used for drug testing. Treatment was delayed until tumors had reached 60-600 mg in mass to correspond to advanced tumors in patients. Drugs being developed for clinical trial by NCI were selected for testing against the xenografts based on promising activity against transplantable murine tumor lines and difference in mechanism of action. Two antimetabolites, PALA and Baker's antifol, a mitotic spindle poison, maytansine, and a DNA intercalating agent, AMSA, produced no significant regression in any of the three colon xenograft lines. From the group of the nitrosoureas, methylCCNU and chlorozotocin were tested. MethylCCNU caused no regression of line HT, a transient response of line CA and complete regressions of line BE. Chlorozotocin also caused regression of line BE but had no effect on the other tumor lines. The results of chemotherapy studies with human colon cancer xenografts in nude mice reflect the clinical situation where few objective responses are achieved with presently available chemotherapy. We would conclude from these studies that information about activity against colon cancer of a new drug may be gained by testing the drug against a panel of human colon cancer xenografts. Careful clinical followup studies and parallel studies with xenograft systems should establish the correlation between individual clinical response and response in the xenograft system.