Methotrexate-albumin conjugate causes tumor growth delay in Dunning R3327 HI prostate cancer-bearing rats

Anticancer Drugs. 1999 Apr;10(4):405-11. doi: 10.1097/00001813-199904000-00009.

Abstract

Based on the rationale of a preferred albumin uptake by tumors, conjugates comprising of rat serum albumin (RSA) as a drug carrier and of methotrexate (MTX) as chemotherapeutic drug were prepared. For a comparative study of MTX-RSA and MTX we chose a slow growing Dunning R3327 HI prostate cancer model. In a radiopharmacologic study blood kinetics and the tumor and organ distribution pattern of residualizingly labeled MTX-RSA were determined, and were found to be similar to that of residualizingly labeled RSA. The MTD was established for Copenhagen rats at a total four injections of 2 mg/kg MTX or MTX-RSA administered at days 0, 4, 8 and 12. Tumor volume measurements and tumor removal showed a small non-significant growth delay in the MTX treatment group, suggesting MTX resistance for the Dunning R3327 HI prostate carcinoma. In contrast, treatment with MTX-RSA resulted in a significant (50%) growth inhibition of the Dunning R3327 HI tumor. The cellular mechanisms responsible for MTX resistance in Dunning HI tumor cells is not known. The improved therapeutic effects seen during MTX-RSA treatment in this slow growing adenocarcinoma might be a result of prolonged tumor exposure time and an altered cellular uptake by a lysosomal route. MTX-albumin conjugates have shown antitumor activity exceeding that of MTX in several tumor xenografts in nude mice, including human prostate cancer. The recently initiated clinical development of MTX-human serum albumin will be continued and cancer of the prostate will be included as a potential target tumor during further clinical phase II testing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Cell Division / drug effects
  • Cell Line
  • Drug Carriers
  • Drug Resistance, Neoplasm
  • Humans
  • Lysosomes / metabolism
  • Male
  • Methotrexate / blood
  • Methotrexate / pharmacokinetics
  • Methotrexate / therapeutic use*
  • Mice
  • Mice, Nude
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology*
  • Rats
  • Serum Albumin / pharmacokinetics
  • Serum Albumin / therapeutic use*
  • Tissue Distribution
  • Transplantation, Heterologous

Substances

  • Drug Carriers
  • Serum Albumin
  • methotrexate-serum albumin
  • Methotrexate