Summary
Escalating doses of DDMP (metoprine) (15–280 mg/m2) were administered as single oral doses 24 h before a fixed leucovorin (CF) rescue (15 mg IM every 6 h for 72 h). CNS toxicity was dose-limiting and cumulative when the drug was given more frequently than at 3-week intervals. DDMP has a very long half-life (150 h) and is extensively bound to serum proteins (88%). It diffuses into the CSF and concentrates in brain tumours and normal brain tissue (brainserum ratio 3.8–5.3). DDMP is a potentially useful drug against brain tumors. Tumor regressions were seen in two patients with epidermoid carcinomas.
Similar content being viewed by others
References
Abelson HT, Gorka C, Fosburg M, Kornblith P (1978) Identification of dihydrofolate reductase in human central-nervous-system tumors. Lancet 1: 184
Alberto O, Peytremann R, Medenica R, Beretta-Piccoli M (1978) Initial clinical experience with a simultaneous combination of 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methylpyrimidine (DDMP) with folinic acid. Cancer Chemother Pharmacol 1: 101
Browman GP, Calvert AH, Taylor GA, Hart LI, Harrap KR (1980a) The intracellular mechanism of action of metoprine (DDMP). Eur J Cancer 16: 1547
Browman GP, Gorka C, Mehta B, Lazarus H, Abelson H (1980b) Studies with a 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methyl-pyrimidine (DDMP)-resistant L1210 leukemia cell line without cross-resistance to methotrexate. Biochem Pharmacol 29: 2241
Currie VE, Young CW (1980) Phase I study of 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methylpyrimidine (metoprine) with and without leucovorin. Proc Am Soc Clin Oncol 21: 359
de Jager R, Rodzynek JJ, Klastersky J, Kenis Y (1978) Phase I study of DDMP (2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methylpyrimidine) and folinic acid (CF) administration. Proc Am Assoc Cancer Res 19: 403
Denlinger RH, Nichol CA, Cavallito JC, Sigel CW (1976) Chemotherapy of primary brain tumors in rats with two lipid soluble diaminopyrimidine folate antagonists. Proc Am Assoc Cancer Res 17: 95
Duch DS, Bigner DD, Bowers SW, Nichol CA (1979) Dihydrofolate reductase in primary brain tumors, cell cultures of central nervous system origin and normal brain during fetal and neonatal growth. Cancer Res 39: 487
Geils GF, Scott CW, Bauch CM, Butterworth CE (1971) Treatment of meningeal leukemia with pyrimethamine. Blood 38: 131
Goldie JH, Harrison SI, Price LA, Hill BT, (1971) Impaired responsiveness to folinic acid protection in methotrexate-resistant L5178Y cells. Eur J Cancer 11: 627
Hamilton L, Philips F, Sternberg S (1954) Hematological effects of certain 2,4-diaminopyrimidines, antagonists of folic acid metabolism. Blood 9: 1062
Hill BT, Price LA (1980) DDMP (2,4-diamino-5-(3′,4′-dichlorophenyl)-methylpyrimidine). Cancer Treat Rev 7: 95
Hill BT, Price LA, Goldie JH (1975) Methotrexate resistance and uptake of DDMP by L5178Y cells. Selective protection with folinic acid. Eur J Cancer 11: 545
Hill BT, Price LA, Harrison SI, Goldie JH (1977) The difference between “selective folinic acid protection” and “folinic acid rescue” in L5178Y cells in culture. Eur J Cancer 13: 861
Hubbel JP, Henning ML, Grace ME, Nichol CA, Sigel CW (to be published) N-Oxide metabolites of the 2,4-diaminopyrimidine inhibitors of dihydrofolate reductase, trimethoprim, pyrimethamine and metoprine. In: Gorrod JW (ed) Biological oxydation of nitrogen. Elsevier North-Holland Biomedical Press Amsterdam, pp 77–182
Levitt M, Nixon PF, Pineus JH (1971) Transport characteristics of folates in cerebrospinal fluid: a study utilising doubly labeled 5-methyl tetrahydrofolate and 5-formyl tetrahydrofolate. J Clin Invest 50: 1301
Miller DS, Rundles RW, Nichol CA, Nichol JL, Wooley JL, Sigel CW (1976) Phase I/II experience with a lipid soluble folate antagonist: 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-metyhlpyrimidine. Proc Am Soc Clin Oncol 17: 263
Murphy M, Ellison RR, Karnofsky DA, Burchenal JH (1954) Clinical effects of the dichloro and monochlorophenyl analogues of diaminopyrimidine: antagonists of folic acid. J Clin Invest 33: 1388
Nichol CA (1967) Studies on dihydrofolate reductase related to the drug sensitivity of microbiologic and neoplastic cells. Adv Enzyme Regul 6: 305
Nichol CA (1977) Pharmacokinetics. Selectivity of action related to physicochemical properties and kinetic patterns of anticancer drugs. Cancer 46: 519
Nichol CA, Cavallito JC, Wooley JL, Sigel CW (1977) Lipid-soluble diaminopyrimidine inhibitors of dihydrofolate reductase. Cancer Treat Rep 61: 559
Price LA, Goldie JH, Hill BT (1975) Methodichlorophen as an antitumor drug: preliminary report. Br Med J 2: 20
Price LA, Hill BT, Goldie JH (1977) DDMP and selective folinic acid protection in the treatment of malignant disease: a further report. Clin Oncol 3: 281
Sirotnak FM, Moccio DM, Dorick DM (1977) Experimental chemotherapy with 5-aryl pyrimidine antifolates: further studies on toxicity and the responsiveness of ascitic, solid and intracranial Sarcoma 180 to DDMP and DDMP with Citrovorum factor. Cancer Treat Rep 61: 1325
Spector R, Lorenzo AV (1975a) Folate transport by the choroid plexus in vitro. Science 187: 540
Spector R, Lorenzo AV (1975b) Folate transport in central nervous system. Am J Physiol 229: 777
Stickney DR, Simmons WS, DeAngelis RL, Rundles RW, Nichol CA (1973) Pharmacokinetics of pyrimethamine (PRM) and 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methylpyrimidine (DDMP) relevant to meningeal leukemia. Proc Am Assoc Cancer Res 14: 52
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
de Jager, R., Dupont, D., Rodzynek, JJ. et al. Phase I clinical trial and pharmacology of 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methylpyrimidine (metoprine) (DDMP) and folinic acid (CF). Cancer Chemother. Pharmacol. 6, 75–80 (1981). https://doi.org/10.1007/BF00253013
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00253013