Burger A M, Bibby M C, Double J A
Clinical Oncology Unit, University of Bradford, UK.
Br J Cancer. 1997;75(4):516-22. doi: 10.1038/bjc.1997.90.
Telomerase, a ribonucleoprotein enzyme, has been found in immortalized but not in most somatic adult human tissues, and thus emerged as a novel target for cancer chemotherapy. However, its usefulness could still be limited by normal tissue toxicity. This study compares enzyme activity in tissues and tumours in conventional in vivo models and human biopsy material, specifically normal human liver, with a view to determining the therapeutic potential of anti-telomerase therapy. The telomeric repeat amplification protocol (TRAP assay) was used to measure enzyme activity and levels were semiquantified by assaying equal concentrations of cellular protein. Telomerase activity was high in the murine embryonic stem cell line CGR8.8, WRL 68 human embryo liver cells, testis, ovary and liver of adult mouse and rat. Low activity was detected in normal human liver, marmoset and pig liver. Very low enzyme activity was seen in mouse, rat and marmoset bone marrow, brain or skin; no activity could be detected in mammalian lung and heart. On the contrary, all 30 human and murine malignant tissues studied showed high to moderate enzyme levels. However, activity found in murine liver was often higher than in tumour, e.g. in the transplantable adenocarcinoma of the colon MAC16. Our findings indicate that telomerase is present not only in murine but also in other normal mammalian tissues such as liver, and that this activity might result from the presence of somatic stem cells. In view of this, the role of telomerase as a potential selective target for therapy needs further investigation. Furthermore, the understanding of regulatory pathways of this enzyme and the selection of screening models will be critical.
端粒酶是一种核糖核蛋白酶，已在永生化细胞中被发现，但在大多数成人体细胞组织中未被发现，因此成为癌症化疗的一个新靶点。然而，其有效性仍可能受到正常组织毒性的限制。本研究比较了传统体内模型和人体活检材料（特别是正常人肝脏）中组织和肿瘤的酶活性，以确定抗端粒酶疗法的治疗潜力。采用端粒重复序列扩增法（TRAP 检测）测量酶活性，并通过检测等量细胞蛋白来半定量酶活性水平。端粒酶活性在小鼠胚胎干细胞系 CGR8.8、WRL 68 人胚胎肝细胞、成年小鼠和大鼠的睾丸、卵巢及肝脏中较高。在正常人肝脏、狨猴肝脏和猪肝中检测到低活性。在小鼠、大鼠和狨猴的骨髓、脑或皮肤中观察到极低的酶活性；在哺乳动物的肺和心脏中未检测到活性。相反，所研究的所有 30 个人类和小鼠恶性组织均显示出高至中等水平的酶活性。然而，在小鼠肝脏中发现的活性通常高于肿瘤中的活性，例如在可移植的结肠腺癌 MAC16 中。我们的研究结果表明，端粒酶不仅存在于小鼠中，也存在于其他正常哺乳动物组织如肝脏中，这种活性可能是由体细胞干细胞的存在导致的。鉴于此，端粒酶作为潜在治疗选择性靶点的作用需要进一步研究。此外，对该酶调控途径的理解以及筛选模型的选择将至关重要。
