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By F. M. Muggia, J. Henney, V. DeVita Jr. (auth.), Professor Georges Mathé, Professor Franco M. Muggia (eds.)

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Normal, rapidly proliferating tissues with an intact active transport system for folates can be protected from death caused by MTX by applying relatively small doses of the antidote CF. This is the so-called rescue effect of CF. Since essentially no CF can enter the cells by passive diffusion at low serum concentrations, tumor cells lacking the active transport system do not benefit from the rescue effect. Figure 2 shows that MTX affects the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by inhibiting the dihydrofolate reductase.

At very high MTX serum concentrations, however, the drug can enter these cells by passive diffusion independent of the active * This work was supported by the Deutsche Forschungsgemeinchaft. We thank Mrs. K. HElL, Mrs. R. SARKAR, Mrs. G. STUPP-POUTOT, and Mrs. U. WUNSCH for their skillful technical assistance Biochemical Control of High-Dose Methotrexate/Leucovorin Rescue Therapy Normal cells with intact transRQ[! ystem D (passive diffusion) MTX Leucovorin - Fig. 1. Principle of high-dose methotrexate (HDMTX) therapy DNA t Cd™P "«I' FH 2 Purine Synthesis (0 C,trovorum factor = 5-Formyl- FH4 =Leucovoron dTR G) (3) Inhibition of dlhydrofolate reductase Reduced C1 pool __ substrate deficiency In thymidylate synthesIs ___ decreased dUR incorporation Into DNA Increased thymidine kinase activity Fig.

In: Salmon SE, Jones SE (eds) Adjuvant therapy cancer II. Grune and Stratton, New York, pp 595-602 40 Paoletti P, Butti G, Casotto A, Grunta F, Knerich R, Marini G, Mazza C, Robustelli della Cuna G, Schiffer D, Soffietti R (1979) Italian multicenter study on malignant brain tumor Adjuvant Therapies of Postsurgical Minimal Residual Disease 41 42 43 44 45 46 47 48 49 50 51 52 53 25 therapy. Proceedings of the international symposium on multidisciplinary aspects of brain tumor therapy. Gardone Riviera, Italy, June 8-10, 1979, P 68 Pinedo HM, Vandrik CPJ, Bramwell VHC, Slooten EA van, Deakin DP, Unnik JAM van, Staquet M, Sylvester R, Bonadonna G (1979) Evaluation of adjuvant therapy in soft tissue sarcoma.

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