MECHANISMS OF NEOPLASTIC TRANSFORMATION IN CULTURED HUMAN CELLS

(1)血淋巴细胞G2期DNA修复的细胞遗传学检测 是发展起来的。通过这种分析，唐氏综合症(DS)和其他癌症一样- 易患遗传性疾病，被证明有G2期DNA修复 缺乏症。(2)在69名接受测试的人中，他们没有已知的癌症倾向 遗传性疾病中，有效修复51例，缺陷修复18例。个人 有缺陷的G2反应有一级和二级亲属 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-的缺陷反应。 辐射与罹患癌症的高风险有关。(3)细胞遗传学 G_2期X-射线照射后损伤部位细胞切割DNA能力的测定 放射治疗表明干皮病的切口活动可以忽略不计 色素沉着(XP)A和D细胞，XP-C水平较高，缺乏 在神经系统疾病中，DS和阿尔茨海默病。结果表明， 这种缺陷可能与神经退行性变有关。(4)人的皮肤 角质形成细胞经ras癌基因恶性转化后显示DNA 修复不足。对照非致瘤细胞和转基因克隆 Ras癌基因以良性肿瘤的形式生长并表达突变的 P21蛋白是修复有效的蛋白。只有那些被转基因的克隆 获得性DNA修复缺陷在裸鼠体内生长为癌症。 Ras癌基因转染后获得缺陷的DNA修复可能 提供从良性到良性进展所需的遗传不稳定性 恶性状态。(5)6名LI家系成员的皮肤成纤维细胞。 Fraumeni综合征表现为G2期修复缺陷，与 3正常对照组。这个家庭的6个成员都有一个抗辐射的 由细胞杀伤决定的表型。成纤维细胞来自于 抗辐射家庭成员表现出相同程度的染色单体损伤 直接在G2期X射线照射后作为辐射敏感者 控制配偶。因此，得出的结论是，辐射敏感性，如 与异步化细胞群中的细胞杀伤率无关 染色体对G2期X射线的敏感性。然而， G2后高频染色单体断裂和缝隙的持续 X相辐射是DNA修复缺陷的一种表现 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.