title: Pre-clinical evaluation of a methotrexate-albumin conjugate (MTX-HSA) in human tumor xenografts in vivo.
abstract: 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.
authors.affiliation: Tumor Biology Center at the University of Freiburg, Breisacherstr. 117, D-79106 Freiburg, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Burger
authors.forename: G
authors.initials: G
authors.lastname: Hartung
authors.forename: G
authors.initials: G
authors.lastname: Stehle
authors.forename: H
authors.initials: H
authors.lastname: Sinn
authors.forename: H H
authors.initials: HH
authors.lastname: Fiebig
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy; D012709:Serum Albumin / Q000009:adverse effects / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D012709:Serum Albumin; C040811:methotrexate-serum albumin; D008727:Methotrexate