Combined effects of adenovirus-mediated wild-type p53 transduction, temozolomide and poly (ADP-ribose) polymerase inhibitor in mismatch repair deficient and non-proliferating tumor cells
Combined effects of adenovirus-mediated wild-type p53 transduction, temozolomide and poly (ADP-ribose) polymerase inhibitor in mismatch repair deficient and non-proliferating tumor cells
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DOI：
10.1038/sj.cdd.4400832
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发表时间：
2001-05-01
影响因子：
12.4
通讯作者：
Graziani, G
中科院分区：
文献类型：
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作者：
Tentori, L;Portarena, I;Graziani, G
p53或错配修复（mismatch repair，MR）功能的缺失和细胞增殖的缺乏通常与肿瘤细胞对甲基化药物的耐药性有关。近年来，抑制聚ADP核糖聚合酶（poly（ADP-ribose）polymerase，PARP）被认为是克服MR缺陷肿瘤对甲基化药物耐药性的一种手段。在本研究中，我们证明了表达p53的腺病毒（Ad-p53）的感染，增强了MR缺陷肿瘤细胞系对甲基化剂替莫唑胺（TZM）的化疗敏感性，无论是作为单一药物使用，还是更有效地与PARP抑制剂结合使用。此外，与药物治疗的Ad-p53的协会诱导了更明显的生长抑制作用比由Ad-p53感染引起的。细胞，生长停滞的p53转导，然后随后暴露于药物，仍然是高度敏感的TZM和PARP抑制剂诱导的细胞毒性。结果表明，这种药物组合可能是有效的，即使在非增殖性肿瘤细胞，这是可以想象的，设想未来可能的策略，以增强由Ad-p53诱导的细胞抑制或细胞毒性效应，基于使用TZM，单独或与PARP抑制剂组合用于治疗耐药肿瘤。
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 cons ide red 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 nonproliferating 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.