TUMOR-LOCALIZATION AND THERAPEUTIC EFFICA CY OF NOVEL METHOTREXATE SERUM-ALBUMIN (MTX-HSA) CONJUGATE IN-VIVO

The massive uptake and catabolism of serum albumin in tumors is well d escribed. The pharmacokinetics of native albumin with a prolonged plas ma half-life and enhanced tumor uptake suggest a possible use as a car rier for tumor therapy. In previous approaches to employ this distribu tion pattern for diagnosis and therapy of neoplastic diseases, albumin molecules were loaded with maximum quantities of cytostatic agents. T o preserve the properties of native albumin and to avoid enhanced phag ocytotic clearance, we used methotrexate-human serum albumin (MTX-HSA) conjugates with the molar loading ratio of 1:1. Using BDIX rats beari ng the O-342 ovarian carcinoma, indirectly radioiodinated MTX-HSA show ed enhanced scintigraphic tumor accumulation, indicating a distinct tu mor localization 48 hours following injection. An average share of 9,9 % of the injected activity was found in the scintigraphic tumor regio n, thus confirming the prominent tumor uptake. In a therapeutic study we compared the tumor volume post treatment and the area-under-the-cur ve of tumor volumes over treatment of animals receiving MTX-HSA treatm ent (0.4 mg MTX/kg) with those receiving saline as placebo. This low d osed MTX-HSA therapy caused significant (p = 0.025) effects on tumor g rowth. It is concluded that MTX-albumin conjugates created with optimi zed labeling techniques and loading ratios cause significant therapeut ic effects even with very low MTX doses. Based on their enhanced tumor uptake these compounds may contribute to improve the efficacy of MTX- therapy.