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

• Published in: The Prostate Vol. 66; no. 8; pp. 858 - 866
• Main Authors: Hao, Xiao-Ke, Liu, Jia-Yun, Yue, Qiao-Hong, Wu, Guo-Jun, Bai, Yu-Jie, Yin, Ying
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-06-2006
• Subjects: ADEPT; Animals; Antibodies, Neoplasm - administration & dosage; Antibodies, Neoplasm - pharmacology; Antibodies, Neoplasm - therapeutic use; carboxypeptidase-A(CPA); 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 (MTX); 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 cancer; 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; scFv; Transplantation, Heterologous
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.20402

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‐α‐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‐α‐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. Prostate 66: 858–866, 2006. © 2006 Wiley‐Liss, Inc.