DESTRUCTION OF WIDR MULTICELLULAR TUMOR SPHEROIDS WITH THE NOVEL THYMIDYLATE SYNTHASE INHIBITOR 1843U89 AT PHYSIOLOGICAL THYMIDINE CONCENTRATIONS

The activity of a novel thymidylate synthase inhibitor, 1843U89, again st WiDr human colon carcinoma multicellular tumor spheroids was invest igated. Continuous exposure of the spheroids to 3 nM 1843U89 for 10 da ys resulted in spheroid disruption, whereas 100 nM methotrexate (MTX) was required for similar effects. Short-term treatment experiments dem onstrated that a 3-day exposure to 100 nM 1843U89 caused spheroid disr uption 9 days after drug removal. A 4-day exposure to 10 nM 1843U89 ca used spheroid disruption 8 days after drug removal. In contrast, treat ment with 10 or 100 nM 1843U89 for 6-48 h or treatment with 1 nM 1843U 89 for up to 5 days caused only growth delay. Continuous exposure of s pheroids to 30 nM 1843U89 in the presence of 0.05 -0.3 mu M thymidine was as effective in causing spheroid disruption as treatment in the ab sence of thymidine, but treatment in the presence of 0.7-3.0 mu M thym idine caused partial reversal of spheroid disruption. The results of t hese experiments suggest that 1843U89 should have potent solid tumor a ctivity in humans but should be less effective in mice due to differen ces in circulating thymidine levels (0.1 vs 1 mu M, respectively).