Selective Cytotoxicity of Carboxypeptidase-activated Methotrexate ex-Peptides
Methotrexate ex-pep tides (derivatives in which an amino acid is linked covalently to the ex-carboxyl of the glutamate residue on the parent drug) can be hydrolyzed by specific carboxypeptidases to yield free Methotrexate (MTX) and the corresponding amino acid. Studies with L12l0 cells in suspension...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
De Gruyter
1989-02-01
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| Series: | Pteridines |
| Online Access: | https://doi.org/10.1515/pteridines.1989.1.1.65 |
| Summary: | Methotrexate ex-pep tides (derivatives in which an amino acid is linked covalently to the ex-carboxyl of the glutamate residue on the parent drug) can be hydrolyzed by specific carboxypeptidases to yield free Methotrexate (MTX) and the corresponding amino acid. Studies with L12l0 cells in suspension culture have shown that the MTX pep tides can serve as "pro-drugs": Because of their inability to be taken up by cells, they are relatively non-toxic. When co-administered with appropriate carboxypeptidases, however, they become equitoxic with MTX. In the present investigation, the potential of the MTX-ala/carboxypeptidase A combination for providing regional cytotoxicity was demonstrated in a model system involving L12l0 cells propagated in semi-solid agarose. When cells and one of the components (MTX peptide or carboxypeptidase) were distributed uniformly throughout the agarose, and the other component was immobilized at the center, a discrete zone of cell kill radiated from the fixed component. These results suggest the possibility of developing a new mode of cancer chemotherapy involving circulating MTX peptides in conjunction with carboxypeptidases linked covalently to tumor-targeted monoclonal antibodies. |
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| ISSN: | 0933-4807 2195-4720 |