Development of PT523 for the treatment of lung cancer

开发PT523治疗肺癌

• 批准号: 6930669
• 负责人: MAREK A WOLTER
• 金额: $ 15.9万
• 依托单位: HANA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-08 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6930669
• 关键词: analog; antineoplastics; athymic mouse; cell line; cell proliferation; combination chemotherapy; dosage; drug interactions; drug screening /evaluation; growth inhibitors; lung neoplasms; methotrexate; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; neoplastic cell; xenotransplantation

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to develop PT523 [Nalpha-(4-amino-4-deoxypteroly)-Ndelta-hemiphthaloyl-L-ornithine], a water soluble, non-polyglutamtable analog of methotrexate (MTX), for the treatment of advanced lung cancer. Lung cancer is among the most commonly occurring malignancies in the world and is one of the few that continues to show an increasing incidence. In the US, lung cancer is the leading cause of cancer death. Most patients with lung cancer present with locally advanced or metastatic disease at the initial diagnosis, and the current standard care for these patients is systemic chemotherapy with a two-drug combination regimen that included a platinum agent. Although the current combination chemotherapy reduces the rate of death attributed to lung cancer, disease progress is inevitable and the dose-limiting toxicities restrict their use. Therefore, development of new combination therapies that aims to inhibit tumor growth and progression while sparing normal cells will improve the quality of life of lung cancer patients. The Specific Aims are: (1) To determine the effect of PT523 in combination with various cytotoxic and targeted therapeutic agents on tumor cell proliferation in vitro. Lung cancer cell lines will be treated with PT523 and various anti-cancer agents alone and in combination for 48 to 96 hours. The cytotoxic agents will include currently approved chemotherapy drugs for lung cancer and targeted therapeutic agents will include small molecule inhibitors for EGFR. The EGFR expression profile in various lung cancer cell lines will be determined by quantitative PCR and immunocytochemistry. The effect of various treatments on lung cancer cell proliferation will be quantified by MTT assay. The agents that work synergistically with PT523 in inhibition of cell growth will be determined. (2) To determine the efficacy of PT523 in combination with various cytotoxic and targeted therapeutic agents on tumor growth in xenograft models. Before evaluating the antitumor activity of PT523 with different agents, the maximum tolerated dose (MTD) of various agents alone or in combination will be determined in athymic mice. The growth inhibition activity of PT523 in combination with various agents will be evaluated in athymic mice bearing human lung carcinomas as s.c. transplants. The agent(s) that are most efficacious in inhibition of tumor growth and best tolerated in combination with PT523 will be selected.

描述（由申请人提供）：该提案的长期目标是开发 PT523 [Nalpha-(4-amino-4-deoxypteroly)-Ndelta-hemipharoyl-L-ornithine]，一种水溶性、非聚谷氨酸类似物甲氨蝶呤（MTX），用于治疗晚期肺癌。肺癌是世界上最常见的恶性肿瘤之一，也是少数发病率持续上升的恶性肿瘤之一。在美国，肺癌是癌症死亡的主要原因。大多数肺癌患者在初次诊断时就出现局部晚期或转移性疾病，目前这些患者的标准治疗是全身化疗，采用包括铂类药物的两种药物组合方案。尽管目前的联合化疗降低了肺癌死亡率，但疾病进展是不可避免的，并且剂量限制性毒性限制了其使用。因此，开发旨在抑制肿瘤生长和进展同时保留正常细胞的新联合疗法将改善肺癌患者的生活质量。具体目标是：（1）确定PT523与各种细胞毒性和靶向治疗药物联合使用对体外肿瘤细胞增殖的影响。肺癌细胞系将用PT523和各种抗癌剂单独或联合处理48至96小时。细胞毒性药物将包括目前批准的肺癌化疗药物，靶向治疗药物将包括EGFR小分子抑制剂。将通过定量PCR和免疫细胞化学测定各种肺癌细胞系中的EGFR表达谱。各种治疗对肺癌细胞增殖的影响将通过MTT测定来量化。将确定与 PT523 协同作用抑制细胞生长的药物。 (2) 确定PT523与各种细胞毒性和靶向治疗药物联合使用对异种移植模型中肿瘤生长的功效。在评估 PT523 与不同药物的抗肿瘤活性之前，将在无胸腺小鼠中确定各种药物单独或组合的最大耐受剂量（MTD）。将在患有人类肺癌的无胸腺小鼠中评估 PT523 与各种药物组合的生长抑制活性。移植。将选择与 PT523 组合时抑制肿瘤生长最有效且耐受性最好的药物。