Combination of caspase transfer using the human telomerase reverse transcriptase promoter and conventional therapies for malignant glioma cells.

Abstract

Recently, we have reported the therapeutic efficacy of delivering initiator caspase (caspase-8) or executioner active caspase (rev-caspase-6) to telomerase-positive malignant glioma cells using the human telomerase reverse transcriptase (hTERT) gene promoter system (hTERT/caspase-8 or hTERT/rev-caspase-6). In the present study, we investigated if conventional treatments for malignant gliomas augment the efficacy of the hTERT/caspase therapy. First, we demonstrated that hTERT/rev-caspase-6 exhibited a greater ability to induce apoptosis in malignant glioma U87-MG and U373-MG cells than hTERT/caspase-8. Next, as conventional treatments to combine with hTERT/rev-caspase-6, apoptosis-inducing agents [cisplatin (CDDP), paclitaxel (PTX), and BCNU] and non-apoptosis-inducing therapies [temozolomide (TMZ) and gamma-irradiation (IR)] were used. Combination of hTERT/rev-caspase-6 gene therapy with PTX yielded a dose-dependent additive effect, while CDDP and BCNU had additive effect only when tumor cells were treated at IC75 of each agent. A decline in the combination effect of CDDP and BCNU at IC50 was due to decreased activity of telomerase in treated tumor cells prior to the hTERT/rev-caspase-6 transfer. On the other hand, TMZ or IR had no significant additive effect on induction of apoptosis. These results suggest that agents, which induce apoptosis without inhibiting telomerase activity are a promising counterpart to combine with hTERT/rev-caspase-6 therapy for the management of malignant gliomas.

• Authors: Hayato Takeuchi, Takao Kanzawa, Yasuko Kondo, Tadashi Komata, Satoshi Hirohata, Satoru Kyo, Seiji Kondo
• Journal: International journal of oncology (Int J Oncol) Vol. 25 Issue 1 Pg. 57-63 (Jul 2004) ISSN: 1019-6439 [Print] Greece
• PMID: 15201989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• Recombinant Fusion Proteins
• Pertussis Toxin
• Telomerase
• Caspases
• Cisplatin
• Carmustine

Topics

• Antineoplastic Agents (pharmacology)
• Carmustine (pharmacology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects, radiation effects)
• Cisplatin (pharmacology)
• DNA-Binding Proteins
• Gamma Rays
• Glioma
• Humans
• Pertussis Toxin (pharmacology)
• Promoter Regions, Genetic (genetics)
• Recombinant Fusion Proteins (metabolism)
• Telomerase (genetics, metabolism)
• Transfection