Tentori Lucio, Portarena Ilaria, Barbarino Marcella, Balduzzi Alessandra, Levati Lauretta, Vergati Matteo, Biroccio Annamaria, Gold Barry, Lombardi Maria Luisa, Graziani Grazia
Department of Neuroscience, University of Rome "Tor Vergata", Rome, Italy.
Mol Pharmacol. 2003 Jan;63(1):192-202. doi: 10.1124/mol.63.1.192.
In the present study, we have investigated the influence of telomerase inhibition in chemosensitivity of melanoma cells to temozolomide (TMZ), a methylating agent with promising antitumor activity against metastatic melanoma. In fact, telomerase, a ribonucleoprotein enzyme expressed in the majority of tumors, is presently considered an attractive target for anticancer therapy, with the double aim of reducing tumor growth and increasing chemosensitivity of cancer cells. Susceptibility to TMZ and to other antitumor agents used for treatment of metastatic melanoma was initially assessed in melanoma lines with different basal levels of telomerase activity. Thereafter, chemosensitivity was investigated after inhibition of telomerase by means of stable transfection of a catalytically inactive, dominant-negative mutant of hTERT (DN-hTERT). This study shows for the first time that: a) susceptibility to TMZ of melanoma lines derived from the same patient did not depend on basal telomerase activity; b) inhibition of telomerase by DN-hTERT resulted in reduced growth rate and increased resistance to TMZ and to the chloroethylating agent carmustine, increased sensitivity to cisplatin, and no change in response to tamoxifen or to a selective N3-adenine methylating agent; c) inhibition of poly(ADP-ribose) polymerase (PARP), an enzyme involved in the repair of N-methylpurines, restored sensitivity of DN-hTERT clones to TMZ. These results indicate that a careful selection of the antitumor agent has to be made when antitelomerase therapy is combined with chemotherapy. Moreover, the data presented here suggest that TMZ + PARP inhibitor combination is active against telomerase-suppressed and slowly growing tumors.
在本研究中，我们调查了端粒酶抑制对黑色素瘤细胞对替莫唑胺（TMZ）化疗敏感性的影响。替莫唑胺是一种甲基化剂，对转移性黑色素瘤具有良好的抗肿瘤活性。事实上，端粒酶是一种在大多数肿瘤中表达的核糖核蛋白酶，目前被认为是抗癌治疗的一个有吸引力的靶点，具有减少肿瘤生长和增加癌细胞化疗敏感性的双重目的。最初在具有不同基础端粒酶活性水平的黑色素瘤细胞系中评估对TMZ和用于治疗转移性黑色素瘤的其他抗肿瘤药物的敏感性。此后，通过稳定转染催化失活的、显性负性hTERT突变体（DN-hTERT）抑制端粒酶后，研究化疗敏感性。本研究首次表明：a）来自同一患者的黑色素瘤细胞系对TMZ的敏感性不依赖于基础端粒酶活性；b）DN-hTERT抑制端粒酶导致生长速率降低，对TMZ和氯乙化剂卡莫司汀的耐药性增加，对顺铂的敏感性增加，对他莫昔芬或选择性N3-腺嘌呤甲基化剂的反应无变化；c）抑制聚（ADP-核糖）聚合酶（PARP），一种参与N-甲基嘌呤修复的酶，可恢复DN-hTERT克隆对TMZ的敏感性。这些结果表明，当端粒酶抑制疗法与化疗联合使用时，必须谨慎选择抗肿瘤药物。此外，此处提供的数据表明，TMZ+PARP抑制剂联合疗法对端粒酶抑制和生长缓慢的肿瘤有效。
