In vitro and in vivo prodrug therapy of prostate cancer using anti-gamma-Sm-scFv/hCPA fusion protein

Prostate. 2006 Jun 1;66(8):858-66. doi: 10.1002/pros.20402.

Abstract

Background: Raising selectivity to tumor cells is a major challenge for most chemotherapy drugs. One of approaches to realizing this goal is antibody-directed enzyme prodrug therapy (ADEPT). This study was done to investigate the curative effect of a new ADEPT system for the treatment of prostate cancer.

Methods: Methotrexate (MTX) prodrugs were synthesized and anti-seminoprotein (SM) single-chain antibody/human carboxypeptidase-A fusion protein (scFv/hCPA) was prepared. Therapeutic effects of this ADEPT system were evaluated.

Results: The synthesis of prodrugs was successful and the prodrugs were confirmed no cytotoxicity, but hydrolysis with tumor-targeted scFv/hCPA fusion protein gave 1,000-fold higher cytotoxicity than MTX-alpha-Phe only. Cell cycle assays showed that tumor cells were arrested in the S phase after ADEPT treatment; furthermore, tumors were inhibited significantly in scFv/hCPA and MTX-alpha-Phe treated mice.

Conclusions: Our results suggest that targeted activation cytotoxicity against established prostate cancer by scFv/hCPA mediated ADEPT is tumor-specific and has no systemic toxicity in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neoplasm / administration & dosage
  • Antibodies, Neoplasm / pharmacology
  • Antibodies, Neoplasm / therapeutic use
  • Carboxypeptidases A / administration & dosage
  • Carboxypeptidases A / immunology
  • Carboxypeptidases A / pharmacology
  • Carboxypeptidases A / therapeutic use*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Drug Delivery Systems*
  • Humans
  • Immunoglobulin Variable Region / administration & dosage
  • Immunoglobulin Variable Region / pharmacology
  • Immunoglobulin Variable Region / therapeutic use
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / analogs & derivatives*
  • Methotrexate / immunology
  • Methotrexate / pharmacology
  • Methotrexate / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplastic Stem Cells
  • Phenylalanine / administration & dosage
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / immunology
  • Phenylalanine / pharmacology
  • Phenylalanine / therapeutic use
  • Prodrugs / administration & dosage
  • Prodrugs / pharmacology
  • Prodrugs / therapeutic use*
  • Prostate-Specific Antigen / immunology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / pharmacology
  • Recombinant Fusion Proteins / therapeutic use*
  • Transplantation, Heterologous

Substances

  • Antibodies, Neoplasm
  • Immunoglobulin Variable Region
  • Prodrugs
  • Recombinant Fusion Proteins
  • methotrexate-alpha-phenylalanine
  • Phenylalanine
  • Carboxypeptidases A
  • Prostate-Specific Antigen
  • Methotrexate