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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neoplasm / administration & dosage
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Antibodies, Neoplasm / pharmacology
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Antibodies, Neoplasm / therapeutic use
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Carboxypeptidases A / administration & dosage
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Carboxypeptidases A / immunology
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Carboxypeptidases A / pharmacology
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Carboxypeptidases A / therapeutic use*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Drug Delivery Systems*
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Humans
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Immunoglobulin Variable Region / administration & dosage
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Immunoglobulin Variable Region / pharmacology
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Immunoglobulin Variable Region / therapeutic use
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Male
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Methotrexate / administration & dosage
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Methotrexate / analogs & derivatives*
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Methotrexate / immunology
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Methotrexate / pharmacology
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Methotrexate / therapeutic use
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Transplantation
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Neoplastic Stem Cells
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Phenylalanine / administration & dosage
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Phenylalanine / analogs & derivatives*
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Phenylalanine / immunology
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Phenylalanine / pharmacology
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Phenylalanine / therapeutic use
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Prodrugs / administration & dosage
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Prodrugs / pharmacology
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Prodrugs / therapeutic use*
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Prostate-Specific Antigen / immunology
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / immunology
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Prostatic Neoplasms / pathology
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / pharmacology
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Recombinant Fusion Proteins / therapeutic use*
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Transplantation, Heterologous
Substances
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Antibodies, Neoplasm
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Immunoglobulin Variable Region
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Prodrugs
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Recombinant Fusion Proteins
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methotrexate-alpha-phenylalanine
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Phenylalanine
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Carboxypeptidases A
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Prostate-Specific Antigen
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Methotrexate