ANTITUMOR-ACTIVITY OF METHOTREXATE-ALBUMIN CONJUGATES IN RATS BEARINGA WALKER-256 CARCINOMA

We have recently reported that albumin accumulates in solid tumors and serves there as a source of nitrogen and energy. Methotrexate-albumin conjugates [:MTX(1)-RSA] derivatized at a molar ratio of 1:1 differ f avor ably from original MTX in terms of plasma presence and tumor upta ke. The purpose of this study was to evaluate the therapeutic efficacy of these novel conjugates in a comparative study with low m.w. MTX in Sprague-Dawley rats bearing a Walker-256 carcinoma. The maximum toler ated dose (MTD) for MTX and MTX(1)-RSA was determined (2 mg/kg based o n MTX injected on days 1, 3 and 8). The tumor-bearing rats received in jections of either the MTD or MTD/2 of MTX, MTX-albumin or mixtures co ntaining the MTD/2 or MTD/4 of both MTX and MTX-albumin. No toxic side effects were observed. Cure rate and tumor growth retardation were sl ightly better for the conjugate compared with MIX alone in the MTD gro up (16 complete remissions vs. 14 of 20 rats). The best results were a chieved for the combination treatment with MTX and MTX-albumin, with c omplete remission in all 20 rats. In conclusion, MTX-albumin conjugate s show therapeutic activity in vivo without toxic side effects. Additi ve effects were observed for a combination of MTX-albumin and MTX. The se effects might be caused by the much longer tumor exposition time of the conjugate in conjunction with a different route of uptake (pinocy tosis for MTX albumin vs. folate receptors for MTX). (C) 1998 Wiley-Li ss, Inc.