ELIMINATION OF EXTRACHROMOSOMAL DNA FROM OVARIAN CANCER

消除卵巢癌中的染色体外 DNA

• 批准号: 2097616
• 负责人: DANIEL D VON HOFF
• 金额: $ 6.69万
• 依托单位: CTRC RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-17 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2097616
• 关键词: cell population study; drug resistance; extrachromosomal DNA; female; gene expression; human subject; human therapy evaluation; hydroxyurea; neoplasm /cancer chemotherapy; neoplastic process; oncogenes; ovary neoplasms

Despite some advances in the use of chemotherapy for treatment of women with ovarian cancer, the majority of women succumb to their disease. In the present project we propose to test a new approach to the modulation of tumor progression and drug resistance in these patients by targeting extrachromosomal DNA. It has long been recognized that double minutes found in metaphase spreads made from human tumors can harbor amplified copies of oncogenes and amplified copies of drug resistance genes. Double minutes are extrachromosomally located DNA which is susceptible to elimination from the cell. We have documented that the antitumor agent hydroxyurea, at clinically achievable concentrations, can eliminate extrachromosomally located double minutes containing amplified oncogenes or amplified drug resistance genes from human tumor cell lines. The first specific aim of the present study is to determine if hydroxyurea given to patients can cause elimination of extrachromosomal DNA from women's ovarian cancer cells. To accomplish this specific aim, women with advanced refractory ovarian cancer with refractory malignant ascites requiring frequent paracentesis for comfort, will be treated with hydroxyurea. The effect of hydroxyurea on the amount of extrachromosomal DNA will be assessed by directly counting the number of double minutes in metaphase spreads as well as by utilizing molecular techniques to measure the amount of circular extrachromosomal DNA both before and after the treatment of the patients with hydroxyurea. Our second specific aim is to determine the effect of hydroxyurea on other ovarian cancer cell parameters including the number and percentage of tumor cells in the ascites, the ability of the cells to clone in soft agar, and, the number of micronuclei per 1000 tumor cells. These parameters will give some indication as to whether or not hydroxyurea is causing a change in cell population phenotype. If hydroxyurea causes a substantial decrease in extrachromosomal DNA in an in vivo situation it is likely that those findings can be used to develop a new therapeutic strategy. Elimination of oncogene containing extrachromosomal DNA by hydroxyurea (or other agents) could modulate tumor progression. Elimination of drug resistance gene containing extrachromosomal DNA could modulate drug resistance.

尽管在使用化学疗法治疗女性方面取得了一些进步 由于卵巢癌，大多数妇女屈服于疾病。 在 我们建议的目前项目以测试一种新的调制方法 通过靶向这些患者的肿瘤进展和耐药性 外染色体DNA。 长期以来已经认识到中期有双分钟 由人类肿瘤制成的差异可以带有癌基因的放大副本 和耐药基因的放大副本。 双分钟是 牙周位置的DNA，易于消除 细胞。 我们已经记录了抗肿瘤剂羟基脲 临床上可实现的浓度可以消除外肿瘤外 位于包含扩增的癌基因或放大药物的双分钟 人类肿瘤细胞系的抗性基因。 本研究的第一个具体目的是确定是否是否 给予患者的羟基脲可能会导致消除肉瘤外体 女性卵巢癌细胞的DNA。 为了实现这一特定目标， 患有早期难治性卵巢癌的女性具有难治性恶性肿瘤 需要经常舒适的腹部需要接受舒适的腹部 羟基脲。 羟基脲对牙外体量的影响 DNA将通过直接计算双分钟数来评估 中期扩散以及利用分子技术测量 在 治疗羟基脲患者。 我们的第二个具体目的是确定羟基脲对 其他卵巢癌细胞参数，包括数量和百分比 腹水中的肿瘤细胞，细胞在软中克隆的能力 琼脂和每1000个肿瘤细胞的微核数量。 这些 参数将表明羟基脲是否为 引起细胞种群表型的变化。 如果羟基脲会导致大量降低。 一个体内的情况，这些发现可能会习惯 制定新的治疗策略。 消除含有癌基因 羟基脲（或其他药物）的外染色体DNA可以调节 肿瘤进展。 消除含有含毒性基因的基因 外染色体DNA可以调节耐药性。