Hypersensitivity of tumor cell lines with microsatellite instability to DNA double strand break producing chemotherapeutic agent bleomycin
Hypersensitivity of tumor cell lines with microsatellite instability to DNA double strand break producing chemotherapeutic agent bleomycin
复制标题
DOI：
10.1158/0008-5472.can-04-0975
复制
发表时间：
2004-07-15
期刊：
影响因子：
11.2
通讯作者：
Malkhosyan, SR
中科院分区：
文献类型：
--
作者：
Li, HR;Shagisultanova, EI;Malkhosyan, SR
DNA错配修复基因的遗传或表观遗传失活导致强突变表型，称为微卫星突变表型或微卫星不稳定性（MSI）。这种突变表型导致负责调节细胞生长和存活/死亡的基因发生突变，从而促进肿瘤的发展和进展。除了这些致瘤性病变外，MSI肿瘤细胞中还发现了其他类型DNA修复基因的突变，例如DNA双链断裂（DNA DSB）修复。我们在这里报道，大多数不同组织来源的msi阳性肿瘤细胞系（子宫内膜癌、卵巢癌、前列腺癌和结直肠癌）对博来霉素（一种产生DNA DSB的化疗药物）过敏。我们认为这种超敏反应可能是由于不同DNA DSB修复基因的同时突变导致DNA DSB修复活性失活的结果。为了为这一假设提供实验支持，我们发现，携带DNA DSB修复基因DNA- pkcs杂合移位突变的msi阳性结直肠癌细胞系HCT-8亚克隆对博来霉素和DNA蛋白激酶抑制剂LY294002的联合治疗比原始HCT-8细胞更敏感，而原始HCT-8细胞是该基因的野生型。这些结果可能有助于设计msi阳性癌症的治疗方法。
Genetic or epigenetic inactivation of DNA mismatch repair genes results in a strong mutator phenotype, known as the microsatellite mutator phenotype or microsatellite instability (MSI). This mutator phenotype causes mutations in genes responsible for the regulation of cell growth and survival/death and thus promotes the development and progression of tumors. In addition to such tumorigenic lesions, mutations in genes of other types of DNA repair, for example, DNA double-strand break (DNA DSB) repair, are found in tumor cells with MSI. We report here that the majority of MSI-positive tumor cell lines of different tissue origins (endometrial, ovarian, prostate, and colorectal carcinomas) are hypersensitive to bleomycin, a DNA DSB producing chemotherapeutic drug. We suggest that this hypersensitivity may be a result of inactivation of the DNA DSB repair activity by concomitant mutations of different DNA DSB repair genes. To provide experimental support to this hypothesis, we show that the subclones of the MSI-positive colorectal cancer cell line HCT-8 that bear heterozygous frameshift mutations in the DNA DSB repair gene DNA-PKCS are more sensitive to a combined treatment with bleomycin and the DNA protein kinase inhibitor LY294002 than the original HCT-8 cells, which are wild type for this gene. These results may be useful in designing therapies for MSI-positive cancer.