TY - JOUR T1 - High Molecular Weight Derivatives of Methotrexate as Chemotherapeutic Agents JF - Molecular Pharmacology JO - Mol Pharmacol SP - 80 LP - 88 VL - 13 IS - 1 AU - BARBARA C. F. CHU AU - JOHN M. WHITELEY Y1 - 1977/01/01 UR - http://molpharm.aspetjournals.org/content/13/1/80.abstract N2 - 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. ACKNOWLEDGMENTS The authors thank Dr. Frank M. Huennekens and Ms. Karin S. Vitols for their critical reviews of this manuscript. ER -