The activity of a novel
thymidylate synthase inhibitor,
1843U89, against WiDr human colon
carcinoma multicellular
tumor spheroids was investigated. Continuous exposure of the spheroids to 3 nM
1843U89 for 10 days resulted in spheroid disruption, whereas 100 nM
methotrexate (MTX) was required for similar effects. Short-term treatment experiments demonstrated that a 3-day exposure to 100 nM
1843U89 caused spheroid disruption 9 days after
drug removal. A 4-day exposure to 10 nM
1843U89 caused spheroid disruption 8 days after
drug removal. In contrast, treatment with 10 or 100 nM
1843U89 for 6-48 h or treatment with 1 nM
1843U89 for up to 5 days caused only growth delay. Continuous exposure of spheroids to 30 nM
1843U89 in the presence of 0.05-0.3 microM
thymidine was as effective in causing spheroid disruption as treatment in the absence of
thymidine, but treatment in the presence of 0.7-3.0 microM
thymidine caused partial reversal of spheroid disruption. The results of these experiments suggest that
1843U89 should have potent solid
tumor activity in humans but should be less effective in mice due to differences in circulating
thymidine levels (0.1 vs 1 microM, respectively).