Brown J M, Wouters B G
Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5468, USA.
Cancer Res. 1999 Apr 1;59(7):1391-9.
A widely held tenet of present day oncology is that tumor cells treated with anticancer agents die from apoptosis, and that cells resistant to apoptosis are resistant to cancer treatment. We suggest, in this review, that this tenet may need to be reexamined for human tumors of nonhematological origin, for two principal reasons: (a) cell killing has often been assessed in short term assays that are more influenced by the rate, than the overall level, of cell killing. This has tended to underestimate cell killing for cells not susceptible to apoptosis or having mutant p53; and (b) conclusions from experiments with normal cells transformed with dominant oncogenes have often been extrapolated to tumor cells. This does not take into account the fact that tumor cells have invariably undergone selection to an apoptotically resistant phenotype. In this review, we examine the impact of these two factors with particular emphasis on the influence of mutations in p53 on the sensitivity of tumor cells to DNA-damaging agents. We find that because wild-type p53 predisposes cells to a more rapid rate of cell death after DNA damage, particularly with normal or minimally transformed cells, that short-term assays have led to the conclusion that mutations in p53 confer resistance to genotoxic agents. On the other hand, if clonogenic survival is used to assess killing in cells derived from actual solid human tumors, then apoptosis and the genes controlling it, such as p53 and bcl-2, appear to play little or no role in the sensitivity of these cells to killing by anticancer drugs and radiation.
当今肿瘤学中一个广泛持有的原则是，用抗癌药物治疗的肿瘤细胞死于凋亡，而对凋亡有抗性的细胞对癌症治疗也有抗性。在本综述中，我们认为，对于非血液学来源的人类肿瘤，这一原则可能需要重新审视，主要有两个原因：（a）细胞杀伤通常在短期试验中进行评估，这些试验更多地受细胞杀伤速率而非总体水平的影响。这往往低估了对凋亡不敏感或具有突变型p53的细胞的杀伤情况；（b）用显性癌基因转化的正常细胞进行的实验得出的结论常常被外推到肿瘤细胞。这没有考虑到肿瘤细胞总是经过选择而具有抗凋亡表型这一事实。在本综述中，我们研究了这两个因素的影响，特别强调了p53突变对肿瘤细胞对DNA损伤剂敏感性的影响。我们发现，由于野生型p53使细胞在DNA损伤后更容易快速死亡，特别是对于正常或轻度转化的细胞，短期试验得出结论认为p53突变赋予对基因毒性剂的抗性。另一方面，如果用克隆形成存活率来评估实际人类实体瘤来源细胞的杀伤情况，那么凋亡及其控制基因，如p53和bcl-2，在这些细胞对抗癌药物和辐射杀伤的敏感性方面似乎作用很小或没有作用。
