Yang B, Eshleman J R, Berger N A, Markowitz S D
Department of Molecular Biology, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Clin Cancer Res. 1996 Oct;2(10):1649-57.
Wild-type p53 is induced by DNA damage. In different cell types, this induction is suggested either to facilitate DNA repair by inducing a cell cycle pause or to potentiate cell death via apoptosis. Wild-type p53 in different cell types has similarly been associated with either enhancement of or increased resistance to the cytotoxicity of many cancer therapeutic agents. We have constructed a colorectal cancer cell line bearing, in addition to endogenous mutant p53 alleles, an exogenous wild-type p53 allele that is under the regulatable control of the lac repressor. Induction of wild-type p53 by isopropyl-beta-thiogalactopyranoside in these cells induces a reversible growth arrest but does not induce cell death. However, we find that the induction of wild-type p53 powerfully potentiates the cytotoxicity of both irradiation and 5-fluorouracil, two agents that are used clinically in the treatment of colorectal cancer. We also find that induction of wild-type p53 potentiates the cytotoxicity of topotecan, a member of the camptothecin family of drugs that also has clinical activity against colon cancer. These findings suggest that the common loss of wild-type p53 in many colorectal cancers may play a role in the clinical resistance of these tumors to anticancer agents. Although some cancer cells may not be directly killed by p53 gene therapy, our findings suggest that genetic alteration of some cancers to induce wild-type p53 may increase their sensitivity to cytotoxic gene therapy.
野生型p53由DNA损伤诱导产生。在不同细胞类型中，这种诱导作用被认为要么通过诱导细胞周期停滞来促进DNA修复，要么通过凋亡增强细胞死亡。不同细胞类型中的野生型p53同样与许多癌症治疗药物细胞毒性的增强或抗性增加有关。我们构建了一种结肠癌细胞系，除了内源性突变p53等位基因外，还携带一个受乳糖阻遏物调控的外源性野生型p53等位基因。在这些细胞中，异丙基-β-硫代半乳糖苷诱导野生型p53会导致可逆的生长停滞，但不会诱导细胞死亡。然而，我们发现野生型p53的诱导会显著增强辐射和5-氟尿嘧啶这两种临床上用于治疗结肠癌的药物的细胞毒性。我们还发现野生型p53的诱导会增强拓扑替康的细胞毒性，拓扑替康是喜树碱类药物家族的一员，对结肠癌也有临床活性。这些发现表明，许多结肠癌中野生型p53的普遍缺失可能在这些肿瘤对抗癌药物的临床抗性中起作用。虽然一些癌细胞可能不会被p53基因治疗直接杀死，但我们的发现表明，诱导某些癌症产生野生型p53的基因改变可能会增加它们对细胞毒性基因治疗的敏感性。
