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Regressions of established breast carcinoma xenografts by carboxypeptidase G2 suicide gene therapy and the prodrug CMDA are due to a bystander effect.

Abstract
The role of the bystander effect in the treatment of a human breast carcinoma xenograft was studied by suicide gene therapy with carboxypeptidase G2 (CPG2) and CMDA. Cells expressing enzymatically active surface-tethered bacterial CPG2 [stCPG2(Q)3] were mixed with control beta-galactosidase (beta-Gal)-expressing cells to give stCPG2(Q)3:beta-Gal ratios of, respectively: group 1, 0:100; group 2, 10:90; group 3, 50:50; and group 4, 100:0. Four days after injection of the cells into nude mice, the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMDA) was administered. Tumor growth delay correlated well with the levels of stCPG2(Q)3 expression: group 1, 0 day delay; group 2, 10 days; group 3, 16 days; and group 4, 90 days. Similarly, the number of cures was strongly correlated to the levels of stCPG2(Q)3 activity: group 1, zero of six cured; group 2, one of six cured; group 3, three of six cured and group 4, four of six cured. There was a good correlation between CPG2 enzyme activity in the tumors and the number of cures. The majority of cells from groups 2 and 3 were apoptotic whereas those from group 1 were not, indicating a substantial bystander effect in the tumors. These results suggest that a bystander effect plays a major role in suicide gene therapy regimens with stCPG2(Q)3 and CMDA.
AuthorsS M Stribbling, F Friedlos, J Martin, L Davies, R A Spooner, R Marais, C J Springer
JournalHuman gene therapy (Hum Gene Ther) Vol. 11 Issue 2 Pg. 285-92 (Jan 20 2000) ISSN: 1043-0342 [Print] United States
PMID10680842 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Glutamates
  • Nitrogen Mustard Compounds
  • Prodrugs
  • 4-((2-chloroethyl)(2-mesyloxyethyl)amino)benzoylglutamic acid
  • gamma-Glutamyl Hydrolase
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Body Weight (drug effects)
  • Breast Neoplasms (drug therapy, genetics)
  • Female
  • Genetic Therapy (methods)
  • Glutamates (pharmacology)
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Nitrogen Mustard Compounds (pharmacology)
  • Prodrugs (pharmacology)
  • Time Factors
  • gamma-Glutamyl Hydrolase (genetics)

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