Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide

Title:	Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide.
Source:	The British journal of cancer [0007-0920] Kanzawa, T yr:2003 vol:89 iss:5 pg:922 -9

Temozolomide (TMZ) is a drug that has proven to be effective in treating malignant gliomas. O6-alkylguanine alkyltransferase (AGT), a DNA repair protein, reduces the antitumor efficacy of TMZ. Therefore cells with low levels of AGT are sensitive to TMZ (U373-MG and U87-MG cells), while cells expressing high levels of AGT are more resistant (T98G). Because it has been demonstrated that chemosensitivity of tumor cells is associated with a decline in telomerase activity, this study investigates whether the responsiveness of malignant glioma cells to TMZ is associated with the level of telomerase activity.

This study assays for cell viability using trypan blue dye exclusion assay, for cell cycle DNA content via FACScan, for telomerase activity via PCR amplification of telomerase extensions, for hTR and hTERT RNA expression (components necessary for telomerase activity) using RT-PCR, and for transcriptional activity of the hTERT promoter-luciferase constructs using a Microtiter Plate Luminometer. And results show that in low levels of AGT, TMZ affects cell viability in a time- and dose- dependent manner, that there appears to be a TMZ induced G2/M arrest in cells, and an inhibition of telomerase activity, hTERT mRNA expression, and transcriptional activity of hTERT promoter. In conclusion, treatment with TMZ inhibits telomerase activity as it interferes with binding sites of a transcription factor, Sp1.

The importance of these findings suggest that TMZ therapy could be determine by monitoring telomerase activity. Therefore the efficacy of TMZ treatment can be quantified.