Combination of caspase transfer using the human telomerase reverse transcriptase promoter and conventional therapies for malignant glioma cells.
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.
Takeuchi
Hayato
H
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Kanzawa
Takao
T
Kondo
Yasuko
Y
Komata
Tadashi
T
Hirohata
Satoshi
S
Kyo
Satoru
S
Kondo
Seiji
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D004268:DNA-Binding Proteins; D005720:Gamma Rays; D005910:Glioma; D006801:Humans; D037342:Pertussis Toxin / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D037342:Pertussis Toxin; D019098:Telomerase; D020169:Caspases; D002945:Cisplatin; D002330:Carmustine