GENE-SPECIFIC THERAPY OF BREAST AND PANCREATIC CANCER

1992年，乳腺癌将侵袭15万美国女性，HER2基因被放大 在晚期和早期乳腺组织中均有约30%的过度表达 肿瘤。胰腺癌将在1992年侵袭3万名美国男性和女性， 几乎对所有患者都是致命的。超过80%的胰腺肿瘤表现为 C-ki-ras癌基因第12位密码子突变。反义和抗基因DNA 治疗学为干预激活的疾病提供了强大的工具 恶性细胞中的致癌基因。这项提议的目标是具体地 抑制HER-2在乳腺癌和突变c-ki-ras中的过表达 在胰腺癌中的表达。三种不同的新型DNA衍生物 将在四种不同的交付模式中使用，以找到一个组合 这将产生最大的效果。DNA衍生品将接受测试 对免疫缺陷小鼠新鲜人肿瘤移植瘤的疗效。 成功的衍生品将准备好进行配方研究和 小/大动物毒理学检测由这笔资金得出结论 句号。在这个项目中，新鲜的人类肿瘤样本将首先被植入 在免疫功能低下的小鼠身上。这些异种移植物将为她进行筛查- 2乳腺组织中的基因扩增和蛋白过度表达 组织。将对胰腺癌移植瘤进行筛查，以确定是否存在 密码子12 c-ki-ras突变体。抑制HER-2蛋白表达，反义 将针对mRNA的5‘端(5’-DCCA ATG GAG GGG)制备DNA Aat)，以及针对小鼠的寡嘌呤-寡嘧啶区域的反基因DNA。 启动子(5‘-dGGGTGGTGGTTTGTGGGT)。抑制c-ki-ras蛋白 表达，反义DNA将针对这两个最常见的 观察到的突变序列(5‘DTAC GCC AAC AGC TCC和5’DTAC GCC ATC AGC TCC)。对于每个序列，DNA硼烷膦酸盐，DNA磷酸二硫酸盐， 以及立体特异的DNA甲基膦酸盐的合成，以及 感觉和混乱的控制。DNA衍生品将被注射 通过腹膜内、口服、微泵输液和静脉注射 在脂质体中。

Breast cancer will attack 150,000 US women in 1992, and HER2 is amplified and overexpressed in about 30% of both advanced and early stage mammary tumors. Pancreatic cancer will attack 30,000 US men and women in 1992 and is fatal in virtually all patients. Over 80% of pancreatic tumors display c-Ki-ras oncogenes with 12th codon mutations. Antisense and antigene DNA therapeutics offer powerful tools for intervention against activated oncogenes in malignant cells. The goal of this proposal is to specifically ablate HER-2 overexpression in breast cancer, and mutant c-Ki-ras expression in pancreatic cancer. Three different novel DNA derivatives will be utilized, in four different delivery modes, to find a combination which will yield maximum efficacy. The DNA derivatives will be tested for efficacy against fresh human tumor xenografts in immunocompromised mice. Successful derivatives will be ready for formulation studies and small/large animal toxicology testing by the conclusion of this funding period. In this project, fresh human tumor samples will first be implanted in immunocompromised mice. These xenografts will then be screened for HER- 2 gene amplification and protein overexpression in the case of breast tissue. Pancreatic cancer xenografts will be screened for the presence of codon 12 c-Ki-ras mutants. To inhibit HER-2 protein expression, antisense DNAs will be prepared against the 5' end of the mRNA(5'-dCCA ATG GAG GGG AAT), and antigene DNAs against an oligopurine-oligopyrimidine region in the promoter (5'-dGGTGGTGGTTGTGGT). To inhibit c-Ki-ras protein expression, antisense DNAs will be prepared against the two most frequently observed mutant sequences (5'dTAC GCC AAC AGC TCC and 5'dTAC GCC ATC AGC TCC). For each sequence, DNA borane phosphonates, DNA phosphorodithioates, and stereospecific DNA methylphosphonates will be synthesized, as well as sense and scrambled controls. The DNA derivatives will be administered intraperitoneally, orally, and by micropump in solution, and intravenously in liposomes.