Methotrexate covalently bound to
human serum albumin in a 1:1 molar ratio (
MTX-HSA) is a new macromolecular
drug which is currently being studied in phase I clinical trials by the German Association for Medical Oncology (AIO) Phase I/II study group. Previous studies have shown that
MTX-HSA differs favorably from unbound MTX in terms of plasma half-life time,
tumor accumulation of
albumin and uptake mechanisms into
cancer cells. To achieve optimal
drug efficacy, repeated treatment cycles were necessary. To evaluate the anti-
tumor activity of
MTX-HSA and MTX in pre-clinical in vivo models, we selected 7 solid human
tumor xenografts growing s.c. in nude mice and administered
drug either i.p. or i.v. weekly for 3 weeks. The maximal tolerated dose (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 significantly more active (p > 0.01) than MTX in 3 models. In the
soft tissue sarcoma SXF 1301,
MTX-HSA effected complete remission/cure after a single injection, whereas free MTX resulted in short-lasting, partial
tumor regression. In the
prostate-cancer model PRXF PC3M,
MTX-HSA produced growth inhibition of 92.8% of control or an optimal test/control (T/C) of 7.2% compared to a T/C of 20.8% for MTX (p = 0.05). In the
osteosarcoma model SXF 1410, optimal T/C values were 10.2% and 14.5%, respectively (p = 0.025). In
lung cancers LXFE 409 and LXFL 529,
bladder cancer BXF 1258 and
breast cancer MAXF 449, both compounds were inactive. The improved
therapeutic effects seen in 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 enhanced permeability and retention effect. Thus, clinical development of
MTX-HSA will continue and
sarcomas as well as
prostate cancers will be included as potential target
tumors for upcoming clinical phase II trials.