Pre-clinical evaluation of a methotrexate-albumin conjugate (MTX-HSA) in human tumor xenografts in vivo

Methotrexate covalently bound to human serum albumin in a I:I molar ratio ( MTX-HSA) is a new macromolecular drug which is currently being studied in p hase I clinical trials by the German Association for Medical Oncology (AlO) Phase I/II study group. Previous studies have shown that MTX-HSA differs f avorably from unbound MTX in terms of plasma half-life time, tumor accumula tion of albumin and uptake mechanisms into cancer cells, To achieve optimal drug efficacy, repeated treatment cycles were necessary, To evaluate the a nti-tumor activity of MTX-HSA and MTX in pre-clinical in vivo models, we se lected 7 solid human tumor xenografts growing s.c. in nude mice and adminis tered drug either i.p. or i.v. weekly for 3 weeks. The maxima[ tolerated do se (MTD) of MTX-HSA in nude mice was 12.5 mg/kg given i.p. on days 1, 8 and 15, whereas the MTD for free MTX was 100 mg/kg given i.v. MTX-HSA was sign ificantly more active (p > 0.01) than MTX in 3 models. In the soft tissue s arcoma SXF 1301, MTX-HSA effected complete remission/cure after a single in jection, whereas free MTX resulted in short-lasting, partial tumor regressi on. In the prostate-cancer model PRXF PC3M, MTX-HSA produced growth inhibit ion of 92.8% of control or an optimal test/control (TIC) of 7.2% compared t o a T/C of 20.8% for MTX (P = 0.05), In the osteosarcoma model SXF 1410, op timal TIC values were 10.2% and 14.5%, respectively (P = 0.025). In lung ca ncers LXFE 409 and LXFL 529, bladder cancer BXF 1258 and breast cancer MAXF 449, both compounds were inactive, The improved therapeutic effects seen i n 3 xenograft models under MTX-HSA treatment are promising and might be due to specific accumulation of the compound in solid tumors owing to their en hanced permeability and retention effect. Thus, clinical development of MTX -HSA will continue and sarcomas as well as prostate cancers will be include d as potential target tumors for upcoming clinical phase II trials, (C) 200 1 Wiley-Liss, Inc.