2004 Fiscal Year Final Research Report Summary
Establishment of novel molecular cancer therapy targeting telomerase and its clinical appication to gynecologic tumors
| Project/Area Number |
15390501
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | Kanazawa University |
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Principal Investigator |
KYO Satoru Kanazawa University, Graduate School of Medical Science, Associate Professor, 医学系研究科, 講師 (50272969)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Masaaki Kanazawa University, University Hospital, Assistant Professor, 医学部付属病院, 助手 (70283140)
KANAYA Taro Kanazawa University, University Hospital, Assistant Professor, 医学部付属病院, 助手 (30303308)
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| Project Period (FY) |
2003 – 2004
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| Keywords | hTERT / Telomerase / Telomere / siRNA / gene therapy / cervical cancer |
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| Research Abstract |
Telomerase activation plays critical roles in tumor growth and progression in part through the maintenance of telomere structure. Indeed, the ubiquitous expression of telomerase in human cancers makes telomerase a promising target for cancer therapy. Genetic, pharmacologic and antisense methods to inhibit telomerase have been described ; however, in most cases, cancer cell death was observed only after many cell divisions. Here, using retroviral delivery of small interfering RHAs specific for the human telomerase reverse transcriptase (hTERT), we successfully inhibited telomerase activity in cervical cancer cell lines. Cells lacking hTERT expression exhibited significantly decreased telomerase activity and showed shortened telomeres and telomeric 3'-overhangs with passage. These cells entered the replicative senescence after considerable number of cell divisions. Notably, the proliferative rate of these cells was significantly impaired, compared to control cells with telomerase activity, even in low passage cells (PD 5). Likewise, colony-forming ability and tumorgenicity in mice were attenuated in low passage cells lacking hTERT. We further examined the effects of chemotherapy and ionizing radiation of cells in which hTERT expression is suppressed. Cells lacking hTERT showed a significantly increased sensitivity than control cells to ionizing radiation or chemotherapeutic agents that induce DNA double strand breaks, such as topoisomerase inhibitors or bleomycin. These findings suggest that a siRNA-based strategy can be applied to the development of novel telomerase inhibitors, whose anti-tumor effects may be enhanced in combination with ionizing radiation and chemotherapy.
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