Sm. Stribbling et al., Regressions of established breast carcinoma xenografts by carboxypeptidaseG2 suicide gene therapy and the prodrug CMDA are due to a bystander effect, HUM GENE TH, 11(2), 2000, pp. 285-292
The role of the bystander effect in the treatment of a human breast carcino
ma xenograft was studied by suicide gene therapy with carboxypeptidase G2 (
CPG2) and CMDA. Cells expressing enzymatically active surface-tethered bact
erial CPG2 [stCPG2(Q)3] were mixed with control beta-galactosidase (beta-Ga
l)-expressing cells to give stCPG2(Q)3:beta-Gal ratios of, respectively: gr
oup 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. Tu
mor 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 d
ays. Similarly, the number of cures was strongly correlated to the levels o
f stCPG2(Q)3 activity: group 1, zero of six cured; group 2, one of six cure
d; 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 t
he tumors. These results suggest that a bystander effect plays a major role
in suicide gene therapy regimens with stCPG2(Q)3 and CMDA.