126 Interactions and cross resistance patterns between various schedules of 5-FU and the new, folate-based thymidilate synthase inhibitor tomudex (D1694)

Abstract

Tomudex (ICI-DI694) is a new, specific inhibitor of thymidilate synthase, based on a folate structure. It has shown promising activity in advanced colorectal carcinoma (response rate 26%). Since it shares the cellular target with 5-FU, the second active drug for colorectal cancer, a detailed evaluation of the interaction of these drugs and of the cross resistance patterns will be important. Methods The human colorectal carcinoma cell lines HT29 and HCT8 were used for the interaction studies; the interactions were evaluated by standard isobologram methodology. Four 5-FU resistant sublines, made resistant to either a 1 h application of 5-FU (HT29-IR, M2-IR) or 24 h application of 5-FU (HT29-24R, M2-24R) were used for the cross resistance studies (AACR 1995, 1889). Cytotoxicity was evaluated by the sulforhodamine-B-assay. Results Tomudex and 5-FU showed partial cross resistance. Tomudex was active in both cell lines with acquired resistance to a 1 h application of 5-FU whereas both cell lines made resistant to 24 h of 5-FU were highly cross resistant to Tomudex. When 5-FU and Tomudex were given simultaneously for 24 h, significant synergistic interactions were seen in both colorectal cancer cell lines. However, when 5-FU was given for 1 h prior to a 24 h incubation of Tomudex, a strong antagonism was seen for higher doses of 5-FU combined with low doses of Tomudex, whereas low doses of 5-FU and high doses of Tomudex proved to be synergistic. Reversing the schedule (24 h Tomudex followed by I h of 5-FU) resulted in synergistic interactions for all ratios of drugs. Conclusions Tomudex exhibits partial cross resistance to 5-FU, especially in cell lines which have been pretreated with protracted schedules of 5-FU. The interactions between Tomudex and 5-FU are schedule dependent. A combination of protracted infusion of 5-FU (e.g. 24 h) and Tomudex appears to be the most active combination. These data might serve as a basis for the design of clinical trials.