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A cell surface tethered enzyme improves efficiency in gene-directed enzyme prodrug therapy.

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.
AuthorsR Marais, R A Spooner, S M Stribbling, Y Light, J Martin, C J Springer
JournalNature biotechnology (Nat Biotechnol) Vol. 15 Issue 13 Pg. 1373-7 (Dec 1997) ISSN: 1087-0156 [Print] United States
PMID9415889 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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