Tentori L, Portarena I, Bonmassar E, Graziani G
Pharmacology and Medical Oncology Section, Department of Neuroscience, University of Rome Tor Vergata, Via di Tor Vergata 135, 00133 Rome, Italy.
Cell Death Differ. 2001 May;8(5):457-69. doi: 10.1038/sj.cdd.4400832.
Lack of p53 or mismatch repair (MR) function and scarce cell proliferation are commonly associated with tumor cell resistance to antineoplastic agents. Recently, inhibition of poly(ADP-ribose) polymerase (PARP) has been considered as a tool to overcome resistance of MR-deficient tumors to methylating agents. In the present study we demonstrated that infection with p53 expressing adenovirus (Ad-p53), enhances chemosensitivity of MR-deficient tumor cell lines to the methylating agent temozolomide (TZM), either used as single agent or, more efficiently, when combined with PARP inhibitor. Moreover, the association of Ad-p53 with drug treatment induced a more pronounced growth inhibitory effect than that provoked by Ad-p53 infection only. Cells, growth arrested by p53 transduction, and then subsequently exposed to the drugs, were still highly susceptible to cytotoxicity induced by TZM and PARP inhibitor. The results suggested that this drug combination might be effective even in non-proliferating tumor cells. It is conceivable to envisage future possible strategies to enhance cytostatic or cytotoxic effects induced by Ad-p53, based on the use of TZM, alone or combined with PARP inhibitor for the therapy of resistant tumors.
缺乏p53或错配修复（MR）功能以及细胞增殖稀少通常与肿瘤细胞对抗肿瘤药物的耐药性相关。最近，抑制聚（ADP - 核糖）聚合酶（PARP）被认为是克服MR缺陷肿瘤对甲基化剂耐药性的一种手段。在本研究中，我们证明用表达p53的腺病毒（Ad - p53）感染可增强MR缺陷肿瘤细胞系对甲基化剂替莫唑胺（TZM）的化学敏感性，TZM既可以单独使用，更有效的是与PARP抑制剂联合使用时。此外，Ad - p53与药物治疗联合使用比仅Ad - p53感染引起的生长抑制作用更明显。通过p53转导使细胞生长停滞，随后暴露于药物时，细胞对TZM和PARP抑制剂诱导的细胞毒性仍高度敏感。结果表明，这种药物组合即使在不增殖的肿瘤细胞中也可能有效。可以设想未来基于单独使用TZM或与PARP抑制剂联合使用来增强Ad - p53诱导的细胞抑制或细胞毒性作用的可能策略，用于耐药肿瘤的治疗。
