Because the apoptotic pathway is often disrupted in
tumor cells, its genetic restoration is a very attractive approach for the treatment of
tumors. To treat
malignant gliomas with this approach, it would be preferred to restrict induction of apoptosis to
tumor cells by establishing a
tumor-specific expression system.
Telomerase is an attractive target because the vast majority of
malignant gliomas have
telomerase activity whereas normal brain cells do not. Activation of
telomerase is tightly regulated at the transcriptional level of the
telomerase catalytic subunit [human
telomerase reverse transcriptase, (hTERT)]. Therefore, we hypothesized that using a hTERT promoter-driven vector system, an apoptosis-inducible gene may be preferentially restricted to
telomerase- or hTERT-positive
tumor cells. In this study, we constructed an expression vector consisting of the constitutively active
caspase-6 (rev-caspase-6) under the hTERT promoter (hTERT/rev-
caspase-6) and then investigated its antitumor effect on
malignant glioma cells. The rationale for using the rev-caspase-6 gene is because it induces apoptosis independent of the
initiator caspases. We demonstrated that the hTERT/rev-
caspase-6 construct induced apoptosis in hTERT-positive
malignant glioma cells, but not in hTERT-negative astrocytes, fibroblasts, and alternative lengthening of telomeres cells. In addition, the growth of s.c.
tumors in nude mice was significantly suppressed by the treatment with hTERT/rev-
caspase-6 construct. The present results strongly suggest that the
telomerase-specific transfer of the rev-caspase-6 gene under the hTERT promoter is a novel targeting approach for the treatment of
malignant gliomas.