Molecular Pharmacology, Vol 13, 80-88, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

High Molecular Weight Derivatives of Methotrexate as Chemotherapeutic Agents

¹ Department of Biochemistry, Scripps Clinic and Research Foundation, La Jolla, California 92037

Female BDF₁ mice treated with methotrexate (MTX) covalently bound to bovine or murine serum albumin (BSA, MSA) show a higher, more prolonged serum concentration and a decreased rate of excretion of MTX compared with a similar group of mice treated with free MTX. Tritiated MTX-albumin derivatives circulate to the tissues as the covalent complexes but are cleaved prior to excretion and exit primarily as unbound MTX. [³H]MTX-albumin derivatives injected intraperitoneally into L1210 tumor-bearing mice results in prolonged localization in the ascitic fluid and elevated intracellular MTX levels after 24 hr. Approximately 90% of the tritium label found in the L1210 cells is located in the cell lysate as free, unmetabolized MTX, whereas when the albumin carrier is labeled with ¹²⁵I, 80% of the radioactivity is found associated with the cell membrane. A single dose of MTX-BSA (equivalent to 15 mg of MTX per kilogram) injected into BDF₁ mice 24 hr after inoculation of 10⁶ L1210 cells is as effective as MTX in prolonging survival time from 8 (control) to 15 days. An equivalent dose of MTX-MSA, however, shows considerable toxicity. MTX-aminoethyldextran derivatives of mol wt 10,000-150,000 are ineffective antitumor agents. These observations suggest that the high molecular weight MTX-albumin derivatives are retained in the serum and extracellular compartments until the complexes are hydrolyzed, and thus markedly increase the lifetime of MTX within the animal.

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ACKNOWLEDGMENTS The authors thank Dr. Frank M. Huennekens and Ms. Karin S. Vitols for their critical reviews of this manuscript.

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