Pre-clinical evaluation of a methotrexate-albumin conjugate (MTX-HSA) in human tumor xenograftsin 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. © 2001 Wiley‐Liss, Inc.

Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside

“…Like many clinical cancers, they are resistant to native methotrexate due to transport deficiencies caused by an epigenetic alteration that down-regulates the expression of the reduced folate carrier (22,23). Hence, in this study, MDA-MB-231 cells were treated with methotrexate bound to albumin (17,24,25), which enters the cells by albuminmediated endocytosis (25) and circumvents the methotrexate transport deficiency of MDA-MB-231 cells. The other cell lines were treated with free methotrexate.…”

Imaging Tumors with an Albumin-Binding Fab, a Novel Tumor-Targeting Agent

“…Based on an observation that tumors catabolize excessive quantities of albumin (14,15), several attempts to use albumin as a carrier for chemotherapeutic agents have been reported (16)(17)(18). In addition, Abraxane, which uses albumin to formulate and solubilize Taxol, is reported to have better biodistribution properties and reduced toxicity relative to other Taxol formulations (42).…”

“…Known to accumulate in and be catabolized by tumors, albumin has previously been pursued as a delivery vehicle for chemotherapy (14)(15)(16)(17)(18). Combining this observation with immunotherapy, we explore the ability of an albumin-binding Fab (AB.Fab) to specifically target tumors.…”

Albumin-Based Drug Delivery as Novel Therapeutic Approach for Rheumatoid Arthritis

“…Using the coupling procedure developed in our laboratory and exerting a 1:1 molar loading ratio, the distribution pattern of the conjugate in vivo is identical with underivated albumin, demonstrating that the native character of the protein is not affected (21,22). Preclinical studies have shown antitumor activity of MTX-HSA in rat tumor models (23,24) and in a variety of human xenograft tumors in nude mice (25). Furthermore, MTX-HSA has shown promising results on the tumor growth, a plasma half-life equivalent to that of HSA, and no immogenicity, and it was well tolerated in a clinical phase I trial for cancer treatment (26).…”