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Abstract. L1210 leukemia was transplanted serially in CDF, mice treated with 5-(3,3-dimethyl-1-triazeno)imidazole4-carboxamide (DIC, NSC 45388). After four different lines (C lines) had been treated for several generations, a marked increase in survival time of untreated mice was observed. In contrast, mice treated with DIC or immunosuppressed with cyclophosphamide succumbed earlier with generalized leukemia. Furthermore, a C line showed unusually high sensitivity to chemotherapeutic treatment with 1,3 bis(2-chloroethyl)-1-nitrosourea. The data suggest that C lines acquired strong antigenicity for CDF, and DBA/2 hosts. DIC treatment may have selected highly antigenic variants or induced somatic mutations resulting in the appearance of strong new transplantation antigen(s).Introduction. The influence exerted by cytotoxic drugs on cell antigens has bcen studied in vitro' and in Vivo.2 Urethan' as well as thalidomide3 seemed to produce antigenic simplification of normal tissue transplantation antigens in vitro. On the other hand, specific changes of tumor transplantation antigens were observed after treatment with 5-fluorouracil in vivo. 2 These observations suggested the possibility that chemoresistant tumor lines4 obtained after long-term treatment with antineoplastic agents might show altered antigenic properties as compared with the original sensitive line. Preliminary experiments with long-transplanted L1210 leukemic lines resistant to 5-(3,3-dimethyl-1-triazeno)imidazole4-carboxamide (DIC, NSC 45388) and also to methotrexate indicated that both were antigenically different from the original sensitive leukemia. Thus, a number of L1210 lines resistant to these drugs has been developed de novo in order to characterize them with respect to tumor transplantation immunity.The present paper describes the growth properties of four distinct DIC-treated lines under various experimental conditions in vivo. The data suggest that leukemic cells acquired rather strong transplantation antigens, foreign to the original host, after a few transplant generations in DIC-treated mice.

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 6 0 6 0 0 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.

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