MECHANISMS OF NEOPLASTIC TRANSFORMATION IN CULTURED HUMAN CELLS

(1)血淋巴细胞G2期DNA修复的细胞遗传学研究 开发了 通过这种检测，唐氏综合症（DS），像其他癌症一样， 易患遗传性疾病，被证明具有G2期DNA修复 缺陷 (2)在69名没有已知癌症倾向的个体中， 遗传性疾病中，51例修复有效，18例修复缺陷。 个人 G2反应缺陷的患者有一级和二级亲属 癌症的平均发病率分别高出3.6倍和2.2倍。 结果表明，这种对G2期X- 辐射与癌症的高风险有关。 (3)细胞遗传学 测定细胞在G2 X-后在受损位点切割DNA的能力 照射表明在干皮病中可忽略不计的切口活性 色素性（XP）A和D细胞，较高水平的XP-C和缺乏 在神经系统疾病，DS和阿尔茨海默病中的应用。 结果提示 这种缺陷可能与神经变性有关。 (4)人体皮肤 ras癌基因恶性转化后的角质形成细胞显示DNA 修复缺陷 对照非致瘤细胞和转染的克隆 ras癌基因，作为良性肿瘤生长，并表达突变的 p21蛋白是修复有效的。 只有那些转染的克隆体 已经获得了DNA修复缺陷，在裸鼠体内生长为癌。 ras癌基因转染后获得缺陷的DNA修复可能 提供了从良性发展到恶性所需的遗传不稳定性， 恶性状态 (5)皮肤成纤维细胞来自6个Li- Fraumeni综合征表现为G2期修复缺陷， 3例正常对照。 这个家庭的所有6名成员都有抗辐射性。 通过细胞杀伤确定的表型。 成纤维细胞来自 放射抗性家族成员表现出相同程度的染色单体损伤 在G2期X射线照射后， 控制配偶 因此，可以得出结论，放射敏感性， 由异步细胞群中的细胞杀伤所决定， 染色体对G2期X射线照射的敏感性。 但 G2后染色单体断裂和间隙的高频率持续存在 相X射线照射是DNA修复缺陷的表现， 与这个家族的癌症倾向有关

(1) A cytogenetic assay for G2 phase DNA repair using blood lymphocytes was developed. with this assay, Down syndrome (DS), like other cancer- prone genetic disorders, was shown to have a G2 phase DNA repair deficiency. (2) Of 69 individuals assayed who had no known cancer-prone genetic disease, 51 had efficient and 18 deficient repair. Individuals with the deficient G2 response had first- and second-degree relatives with a 3.6- and 2.2-fold higher mean frequency of cancer, respectively. The results suggest that this deficient response to G2 phase X- irradiation is associated with a high risk of cancer. (3) A cytogenetic assay for capacity of cells to incise DNA at damaged sites after G2 X- irradiation indicated negligible incision activity in xeroderma pigmentosum (XP) A and D cells, a higher level in XP-C and a deficiency in neurologic diseases, DS and Alzheimer's disease. Results suggest that this deficiency may be associated with neurodegeneration. (4) Human skin keratinocytes after malignant transformation by ras oncogene showed a DNA repair deficiency. Control non-tumorigenic cells and clones transfected with ras oncogene that grew as benign tumors and expressed the mutated p21 protein were repair-efficient. Only those transfected clones that had acquired the DNA repair deficiency grew as carcinomas in nude mice. Acquisition of deficient DNA repair after ras oncogene transfection may provide the genetic instability required for progression from benign to malignant state. (5) Skin fibroblasts from 6 family members with Li- Fraumeni syndrome showed the G2 phase repair deficiency in contrast to 3 normal controls. All 6 members of the family had a radioresistant phenotype as determined by cell killing. Fibroblasts from a radioresistant family member showed the same extent of chromatid damage directly after G2 phase X-irradiation as those from the radiosensitive control spouse. It is concluded, therefore, that radiosensitivity, as determined by cell killing in asynchronous cell populations is unrelated to chromosomal sensitivity to G2 phase X-irradiation. However, the persistence of a high frequency of chromatid breaks and gaps after G2 phase X-irradiation, a manifestation of deficient DNA repair, is associated with cancer-proneness in this family.