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

Int J Cancer. 2001 Jun 1;92(5):718-24. doi: 10.1002/1097-0215(20010601)92:5<718::aid-ijc1257>;2-d.


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.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Drug Evaluation
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Methotrexate / adverse effects
  • Methotrexate / therapeutic use*
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy*
  • Prostatic Neoplasms / drug therapy
  • Sarcoma / drug therapy
  • Serum Albumin / adverse effects
  • Serum Albumin / therapeutic use*
  • Transplantation, Heterologous


  • Antineoplastic Agents
  • Serum Albumin
  • methotrexate-serum albumin
  • Methotrexate