Regressions of established breast carcinoma xenografts by carboxypeptidase G2 suicide gene therapy and the prodrug CMDA are due to a bystander effect.
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.
Stribbling
S M
SM
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Friedlos
F
F
Martin
J
J
Davies
L
L
Spooner
R A
RA
Marais
R
R
Springer
C J
CJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005971:Glutamates / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D013997:Time Factors; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics*
D000970:Antineoplastic Agents; D005971:Glutamates; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C092574:4-((2-chloroethyl)(2-mesyloxyethyl)amino)benzoylglutamic acid; D011623:gamma-Glutamyl Hydrolase