In vitro and in vivo prodrug therapy of prostate cancer using anti-gamma-Sm-scFv/hCPA fusion protein.
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.
Hao
Xiao-Ke
XK
Department of Clinical Laboratory, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Liu
Jia-Yun
JY
Yue
Qiao-Hong
QH
Wu
Guo-Jun
GJ
Bai
Yu-Jie
YJ
Yin
Ying
Y
D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D043422:Carboxypeptidases A / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000276:immunology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000912:Antibodies, Neoplasm; D007135:Immunoglobulin Variable Region; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; C091716:methotrexate-alpha-phenylalanine; D010649:Phenylalanine; D043422:Carboxypeptidases A; D017430:Prostate-Specific Antigen; D008727:Methotrexate