Abstract |
The potential for expressing the bacterial enzyme carboxypeptidase G2 (CPG2) tethered to the outer surface of mammalian cells was examined for use in gene-directed enzyme prodrug therapy. The affinity of CPG2 for the substrate methotrexate was unaffected by three mutations required to prevent N-linked glycosylation. Breast carcinoma MDA MB 361 cells expressing CPG2 internally showed only a very modest increase in sensitivity to the prodrug CMDA because the prodrug did not enter the cells. Cells expressing surface-tethered CPG2, however, became 16-24-fold more sensitive to CMDA and could mount a good bystander effect. Systemic administration of CMDA to mice bearing established xenografts of the transfected cells led to sustained tumor regressions or cures.
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Authors | R Marais, R A Spooner, S M Stribbling, Y Light, J Martin, C J Springer |
Journal | Nature biotechnology
(Nat Biotechnol)
Vol. 15
Issue 13
Pg. 1373-7
(Dec 1997)
ISSN: 1087-0156 [Print] United States |
PMID | 9415889
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimetabolites, Antineoplastic
- Antineoplastic Agents
- Glutamates
- Membrane Proteins
- Nitrogen Mustard Compounds
- Prodrugs
- 4-((2-chloroethyl)(2-mesyloxyethyl)amino)benzoylglutamic acid
- gamma-Glutamyl Hydrolase
- Methotrexate
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Topics |
- 3T3 Cells
- Animals
- Antimetabolites, Antineoplastic
(chemistry, pharmacology)
- Antineoplastic Agents
(pharmacology)
- Breast Neoplasms
(drug therapy, pathology)
- Drug Delivery Systems
- Female
- Gene Expression Regulation, Enzymologic
(genetics)
- Glutamates
(chemistry, pharmacology)
- Glycosylation
- Humans
- Membrane Proteins
(biosynthesis)
- Methotrexate
(chemistry, pharmacology)
- Mice
- Mice, Nude
- Mutation
(genetics)
- Neoplasm Transplantation
- Nitrogen Mustard Compounds
(chemistry, pharmacology)
- Prodrugs
(pharmacology)
- Transfection
- Tumor Cells, Cultured
(drug effects)
- gamma-Glutamyl Hydrolase
(biosynthesis, chemistry, pharmacology)
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