Caporaso Patrizia, Turriziani Mario, Venditti Adriano, Marchesi Francesco, Buccisano Francesco, Tirindelli Maria Cristina, Alvino Ester, Garbin Alberto, Tortorelli Grazia, Toppo Laura, Bonmassar Enzo, D'Atri Stefania, Amadori Sergio
Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy.
DNA Repair (Amst). 2007 Aug 1;6(8):1179-86. doi: 10.1016/j.dnarep.2007.03.016. Epub 2007 May 17.
Previous studies indicated that dacarbazine and Temozolomide could be highly effective against refractory acute leukaemia. Their activity relies mainly on the generation of methyl adducts at the O(6)-position of guanine in DNA. High levels of O(6)-methylguanine-DNA methyltransferase (MGMT) or a defective mismatch repair (MMR) system, are associated with cellular resistance to triazenes. The MGMT inhibitor, O(6)-(4-bromothenyl)guanine (Lomeguatrib), can restore in vitro sensitivity to Temozolomide in MMR-proficient blasts. In the early 1970s we discovered that, in vivo, triazene compounds induce the appearance of novel transplantation antigens in murine leukaemia ("Chemical Xenogenization", CX). Non-self peptides presented by class I MHC molecules are generated by triazene-induced somatic mutations, affecting retroviral sequences that are detectable in the mouse genome. Moreover, preliminary experiments suggested that human cancer cells can also undergo CX. Therefore, we designed a chemo-immunotherapy strategy in leukaemic patients as follows: (a) cytoreduction and a hypothetical CX phase, i.e. treatment with Lomeguatrib (to suppress MGMT activity) and Temozolomide (to kill sensitive blasts and to presumably induce CX in resistant leukaemic cells); (b) immune response recovery phase using interleukin-2 (to possibly restore an immune response and take advantage of the hypothetical, triazene-induced CX). Here we present the results of pilot study which is in progress in patients with refractory/relapsed acute leukaemia. In all tested cases, Lomeguatrib suppressed MGMT activity in vivo. Six out of eight patients showed partial or complete disappearance of blast cells in peripheral blood or in bone marrow. We observed severe and long-lasting myelosuppression, accompanied by limited non-haematological toxicity. Up to now, two patients are alive (after 9 and 10 months, respectively), four died of opportunistic infections and two of progressive disease. This investigation confirms the potential role of triazenes in leukaemia and highlights the contribution of Lomeguatrib in overcoming drug resistance. Further studies are required to establish whether Temozolomide can induce CX in human leukaemia, and thus offer a new approach to control minimal residual disease.
先前的研究表明，达卡巴嗪和替莫唑胺对难治性急性白血病可能非常有效。它们的活性主要依赖于在DNA中鸟嘌呤的O(6)位生成甲基加合物。高水平的O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）或缺陷的错配修复（MMR）系统与细胞对三氮烯的耐药性有关。MGMT抑制剂O(6)-(4-溴噻吩基)鸟嘌呤（洛美胍曲）可在体外恢复MMR功能正常的原始细胞对替莫唑胺的敏感性。20世纪70年代初，我们发现，在体内，三氮烯化合物可诱导小鼠白血病中出现新的移植抗原（“化学异种化”，CX）。I类MHC分子呈递的非自身肽是由三氮烯诱导的体细胞突变产生的，这些突变影响可在小鼠基因组中检测到的逆转录病毒序列。此外，初步实验表明人类癌细胞也可发生CX。因此，我们为白血病患者设计了如下化学免疫治疗策略：(a) 细胞减灭和假设的CX阶段，即使用洛美胍曲（抑制MGMT活性）和替莫唑胺（杀死敏感原始细胞并可能在耐药白血病细胞中诱导CX）进行治疗；(b) 使用白细胞介素-2的免疫反应恢复阶段（可能恢复免疫反应并利用假设的、三氮烯诱导的CX）。在此，我们展示了一项针对难治性/复发性急性白血病患者正在进行的初步研究结果。在所有测试病例中，洛美胍曲在体内抑制了MGMT活性。8名患者中有6名在外周血或骨髓中显示原始细胞部分或完全消失。我们观察到严重且持久的骨髓抑制，并伴有有限的非血液学毒性。截至目前，两名患者存活（分别为9个月和10个月后），四名死于机会性感染，两名死于疾病进展。这项研究证实了三氮烯在白血病中的潜在作用，并突出了洛美胍曲在克服耐药性方面的作用。需要进一步研究以确定替莫唑胺是否能在人类白血病中诱导CX，从而为控制微小残留病提供一种新方法。
