Summary
Clinical and pharmacologic effects of dichloromethotrexate (DCM) were reevaluated by an intermittent intravenous large dose schedule in patients with advanced malignancies. DCM was tolerated without Leucovorin (calcium folinate) in man, even when the initial immunoassayable DCM level approached 10-3 M. Hepatic dysfunction occurred more frequently at high doses. Hematologic toxicity was not dose-limiting. Plasma decay of DCM was comparable to that of methotrexate (MTX). Of 50 patients treated, five including two with hepatic metastasis from colon carcinoma, responded with more than 50% regression of tumor.
In vitro comparison of DCM and MTX in Molt 3 cells revealed that DCM was slightly more inhibitory than MTX on an equimolar basis. In the presence of 2.5 g/dl of human serum albumin (HA), however, inhibitory effects of DCM decreased markedly. The decreased biologic effects of DCM compared to those of MTX are due to much higher binding to HA by DCM. This phenomenon appears to explain all of the clinical and pharmacologic characteristics of DCM.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Band PR, Ross CA, Holland JF (1973) Comparison of two dose schedules of dichloromethotrexate (NSC-29630) in lung cancer. Cancer Chemother Rep 57:79–82
Brockman RW (1974) Mechanism of resistance. In: Sartorelli AC, Johns DG (eds) Antineoplastic and immunosuppressive agents. Springer, New York, pp 352–410
Condit PT, Chanes RE, Joel W (1969) Renal toxicity of methotrexate. Cancer 23:126–131
Davidson JD, Oliverio VT (1963) The physiologic disposition of dichloromethotrexate-Cl36 in man. Clin Pharmacol Ther 6:321–323
Djerassi I, Rominger J, Kim JS, Turchi J, Suvansri U, Hughes D (1972) Phase I study of high doses of methotrexate with citrovorum factor in patients with lung cancer. Cancer 30:22–30
Fernbach B, Ohnuma T, Takahashi I, Greenspan EM, Holland JF (1979) Reevaluation of dichloromethotrexate. Proc Am Assoc Cancer Res and Am Soc Clin Oncol 20:163
Frei E III, Spurr CL, Brindley CO, Selawry O, Holland JF, Rail DR, Wasserman LR, Hoogstraten B, Shnider BI, Mclntyre OR, Matthews LB Jr, Miller SP (1965) Clinical studies of dichloromethotrexate (NSC 29630). Clin Pharmacol Ther 6:160–171
Goldin A, Humphreys SR, Venditti JM, Mantel N (1959) Prolongation of life span of mice with advanced leukemia (L1210) by treatment with halogenated derivatives of amethop- terin. J Natl Cancer Inst 22:811–823
Goldin A, Venditti JM, Klein I, Mantel N (1966) Eradication of leukemic cells L1210 by methotrexate and methotrexate plus citrovorum factor. Nature 212:1548
Isacoff WH, Morrison PF, Aroesty J, Willis KL, Block JB, Lincoln TL (1977) Pharmacokinetics of high dose methotrexate with citrovorum factor rescue. Cancer Treat Rep 61:1665–1674
Jaffe N, Frei E III, Traggis D, Bishop Y (1974) Adjuvant methotrexate and citrovorum factor treatment of osteogenic sarcoma. N Engl J Med 291:994–997
Levitt M, Mosher MB, DeConti RC, Farber LR, Skeel RT, Marsh JC, Mitchell MS, Papac RJ, Thomas ED, Bertino JR (1973) Improved therapeutic index of methotrexate with “Leucovorin rescue.” Cancer Res 33:1792–1734
Ohnuma T, Arkin H, Minowada J, Holland JF (1978) Differential chemotherapeutic susceptibility of human T-lymphocytes and B-lymphocytes in culture. J Natl Cancer Inst 60:749–752
Ohnuma T, Nogeire C, Cuttner J, Holland JF (1978) Phase I study with neocarzinostatin: Tolerance to two hour infusion and continuous infusion. Cancer 42:1670–1679
Takahashi I, Ohnuma T, Holland JF (1979) A comparison of the biological effects of dichloromethotrexate and methotrexate on human leukemic cells in culture. Cancer Res 39:1264–1268
Vogel CI, Adamson RH, DeVita VT, Johns DG, Kyalwazi SK (1972) Preliminary clinical trials of dichloromethotrexate (NSC-29630) in hepatocellular carcinoma. Cancer Chemother Rep 56:249–258
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1980 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Fernbach, B., Takahashi, I., Ohnuma, T., Holland, J.F. (1980). Clinical and Laboratory Reevalution of Dichloromethotrexate. In: Mathé, G., Muggia, F.M. (eds) Cancer Chemo- and Immunopharmacology. Recent Results in Cancer Research, vol 74. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-81488-4_8
Download citation
DOI: https://doi.org/10.1007/978-3-642-81488-4_8
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-81490-7
Online ISBN: 978-3-642-81488-4
eBook Packages: Springer Book Archive