Kido A, Tsujiuchi T, Morishita T, Tsutsumi M, Takahama M, Miyauchi Y, Mii Y, Tamai S, Konishi Y
Department of Oncological Pathology, Nara Medical University.
Jpn J Cancer Res. 1998 Oct;89(10):1074-81. doi: 10.1111/j.1349-7006.1998.tb00499.x.
To determine the role of telomerase activity in the growth of tumors in rats undergoing chemotherapy, a comparison of the volumes of telomerase-positive transplantable osteosarcomas was made in rats treated with the antineoplastic agent cis-diammine dichloroplatinum (CDDP) or the angiogenesis inhibitor O-(chloroacetylcarbamoyl)fumagillol (AGM-1470). Male F344 rats, 8 weeks old, received transplants of macroscopic lung metastatic nodules into the subcutaneous back space and treatment was started on day 14 thereafter. CDDP was injected i.v. at doses of 0, 0.625, 1.25 and 2.5 mg/kg body weight (b.w.) and AGM-1470 was administered at total doses of 0, 2.5, 5 and 10 mg/kg b.w. over 2 weeks by osmotic pumps, also implanted into the subcutaneous back space, but remote from the transplanted tumors. On day 28, all animals were killed for measurement of transplanted tumor size and determination of telomerase activities by telomeric repeat amplification protocol (TRAP) assay. The results showed telomerase activity to be highly correlated with the treated/non-treated (T/C) tumor size ratio (r = 0.96, P < 0.0001). In a second experiment, CDDP at 2.5 mg/kg b.w. and AGM-1470 at 10 mg/kg b.w., these being the most effective doses, were given as in the first experiment, and animals were serially killed on days 14, 21, 28, 35 and 42. Tumors in rats treated with CDDP and AGM-1470 showed 18.2% and 20.5% of the control telomerase activity on days 35 and 21, respectively, when tumor growth was inhibited. However, on day 42, the activities increased to 46.5% and 92.5%, this correlating with re-growth (r = 0.73, P < 0.0001). These results suggest that decline of telomerase activity may be involved in tumor growth retardation induced by chemotherapeutic agents. This possibility clearly warrants further mechanistic studies.
为了确定端粒酶活性在接受化疗的大鼠肿瘤生长中的作用，对用抗肿瘤药物顺二氨二氯铂（CDDP）或血管生成抑制剂O-(氯乙酰氨甲酰基)烟曲霉素（AGM-1470）治疗的大鼠中端粒酶阳性可移植骨肉瘤的体积进行了比较。8周龄的雄性F344大鼠在背部皮下间隙接受肉眼可见的肺转移结节移植，此后第14天开始治疗。CDDP以0、0.625、1.25和2.5mg/kg体重（b.w.）的剂量静脉注射，AGM-1470通过渗透泵在2周内以0、2.5、5和10mg/kg b.w.的总剂量给药，渗透泵也植入背部皮下间隙，但远离移植肿瘤。在第28天，处死所有动物以测量移植肿瘤大小，并通过端粒重复扩增协议（TRAP）测定法测定端粒酶活性。结果显示端粒酶活性与治疗/未治疗（T/C）肿瘤大小比高度相关（r = 0.96，P < 0.0001）。在第二个实验中，按照第一个实验的方式给予2.5mg/kg b.w.的CDDP和10mg/kg b.w.的AGM-1470，这是最有效的剂量，并在第14、21、28、35和42天连续处死动物。用CDDP和AGM-1470治疗大鼠的肿瘤在第35天和第21天分别显示对照端粒酶活性的18.2%和20.5%，此时肿瘤生长受到抑制。然而，在第42天，活性增加到46.5%和92.5%，这与肿瘤再生长相关（r = 0.73，P < 0.0001）。这些结果表明端粒酶活性的下降可能与化疗药物诱导的肿瘤生长迟缓有关。这种可能性显然值得进一步进行机制研究。
