Methotrexate toxicity in down syndrome : investigation of thymidylate synthetase and thymidine kinase pathways

Marie A. Peeters and Jérôme Lejeune.

Fourth international down syndrome convention. Jerusalem 19-24 mars 1989


Sommaire

There is now ample evidence, both clinical and in vitro that patients with Down syndrome (DS) are unusually sensitive to the dihydrofolate reductase inhibitor: methotrexate (MTX). Investigating the pathophysiological mechanisms responsibly: for their characteristic increased MTX sensitivity, we studied the "de novo" and the "salvage" pathways of thymidine monophosphate (TMP) synthesis in 9 patients with DS and 9 healthy control sibs. Using an in vitro assay preciously described (1), we added FUdR (0.1 x 10-8M, 2 X 10 -8 M, 20 X 10 -8M) , an inhibitor of thymidylat synthetase to peripheral blood lymphocyte cultures to study de novo TMP synthesis. At the different doses of FUdR, there was a significant dose-related decrease in mitotic index (MI) in both DS and control lymphocytes, which was similar in both groups. The decrease was only partially alleviated by the addition of exogenous thymidine. The salvage pathway for TMP synthesis (via thymidine kinase) was investigated by adding exogenous thymidine (15 X 10-6 M) to rescue lymphocyte cultures from MTX cytotoxicity (1.2 X 10-8M and 2.4 X 10-8 M). The adjunction of thymidine alone to the culture medium did not modify the MI in either DS or control cultures. In the presence of MTX, exogenous thymidine rescued both normal and DS lymphocytes from thymineless death. These findings suggest that there Is no underlying intrinsic defect of either thymidylate synthetase or of thymidine kinase which could account for the increased MTX toxicity observed in patients with DS.


Haut

(1) Lejeune J. et al. Ann Génét 1986, 29: 16-19.