Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA

Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53

“…As shown in Figure 2, the antitumor effect of 2-5A-anti-hTR treatment was remarkable in all six cell lines, as expected from the results we previously reported. 29,30 The viability of tumor cells was reduced between 20 and 70% after 4 days treatment with 2-5A-anti-hTR in the presence of lipofectamine. The cytotoxic effect of lipofectamine alone or control oligonucleotides with six mismatched nucleotides 29 mixed with lipofectamine was minimal (data not shown).…”

“…29,30 The viability of tumor cells was reduced between 20 and 70% after 4 days treatment with 2-5A-anti-hTR in the presence of lipofectamine. The cytotoxic effect of lipofectamine alone or control oligonucleotides with six mismatched nucleotides 29 mixed with lipofectamine was minimal (data not shown). Among the adenoviral treatment, the p53 transfer showed higher cytotoxicity than p16 or p21 treatment.…”

“…Previously, we demonstrated that treatment with 2-5A-anti-hTR induced apoptosis in malignant glioma cells. 29 Malignant glioma cells, in addition, underwent apoptosis following the introduction of wild-type p53 gene. 8,9 Therefore, we speculated that the combination effect might be mainly due to induction of apoptosis.…”

“…Recently, it has been demonstrated that targeting the RNA template of telomerase (hTR) with antisense RNA [22][23][24][25] or inhibiting the function of a catalytic protein subunit of telomerase (hTERT) with a dominant-negative mutant [26][27][28] showed a significant antitumor effect. We have recently synthesized a 19-mer antisense oligonucleotide against hTR linked 2-5A (5′-phosphorylated 2′-5′-linked oligoadenylate) (2-5A-anti-hTR) and demonstrated its cytotoxic effect on malignant glioma cells 29,30 or prostate cancer cells. 31 The effect of 2-5A-antihTR was mainly due to induction of apoptosis.…”

Gene therapy in the CNS

“…This includes use of replication-conditional viruses that kill tumor cells by lytic replication, including E1b-minus adenovirus, which replicates preferentially in cells with mutant p53, 218 and TK-minus and ribonucleotide reductase-minus HSV, which require compensatory cellular enzymes up-regulated in dividing cells to replicate. 5,219 Other weapons include: activation of the tumor necrosis factor receptor 220 or other ligands which trigger apoptosis; antisense against telomerase, which protects the ends of chromosomes; 221 targeting of a glioma-specific chloride channel, 222 and fusion of adjacent cells to form a multinucleated, necrotic mass. 223 Gene therapy offers potential ways to tackle both the invasive nature of glioblastoma and their unique properties, and one can envision a multicomponent therapeutic strategy ( Figure 3).…”