[Evaluation of biochemical criteria for sensitivity of tumor cells to methotrexate by means of mathematic simulation]. / Otsenka biokhimicheskikh kriteriev chuvstvitel'nosti opukholevykh kletox k metotreksatu s pomoshch'iumetodov matematicheskogo modelirovaniia.

A mathematical model of the folic acid cycle and of thymidylate, purines, methionine and serine biosynthetic reactions in leukemia L-1210 and Ehrlich ascite tumour cells was developed. This model was used for an analysis of biochemical criteria of different sensitivity of these tumours to methotrexate, such as differences in the rates of methotrexate transport into the cells, levels of target enzyme, dihydrofolate reductase, its affinity for the inhibitor and the capacity of "salvage" pathways of tetrahydrofolate formation. It was shown that low sensitivity of the Ehrlich ascite tumour cells to methotrexate is due to mainly a high activity of methionine synthetase, which represents a "salvage" pathway of tetrahydrofolic acid regeneration in the presence of methotrexate. The results of this analysis were used to predict a combined utilization of methotrexate and methionine synthetase inhibitor. The pretreatment of the tumour cells of the methionine synthetase inhibitor enhances the effects of methotrexate on the thymidylate and purines syntheses, thus increasing their sensitivity to this drug.

[Mathematical description and study of the folic acid cycle reactions]. / O matematicheskom opisanii i issledovanii zakonomernostei funktsionirovaniia tsikla folievoi kisloty.

A general description of the folic acid cycle and associate reactions of thymidilate, purines, methionine and serine biosyntheses is presented as a system of differential equations. The concrete models of this reaction complex as well as methotrexate transport into the leukemia L 1210 and Ehrlich ascite tumour cells and the dynamic inhibition of the target enzyme--dihydrofolate reductase--by methotrexate have been described and investigated. The adequacy of mathematical models to the experimental data has been demonstrated.