Camptothecin Analogs for Cancer Therapy

描述(由申请人提供)：7-丁基-10-氨基喜树碱(BACPT)是一种新型的喜树碱类似物，它是一种水溶性二肽前体药物-BACPTDP，可增加缺氧/酸性肿瘤组织的活性，这种肿瘤以快速生长的癌症为特征，其特征是血管系统不足，无法生长。体外和体内研究均支持BACPTDP在胰腺癌治疗中的潜在用途。BACPTDP在人PANC-1异种移植模型中与其他CPT对照相比的显著反应被综述，以支持本申请中提议的临床前研究。这项第二阶段研究的具体目标是：1.合成10-20克的7-丁基-10-氨基喜树碱二肽(BACPTDP)--足以用于临床前研究和制剂研究。2.进行小鼠和狗的毒性和药代动力学研究。3.将药物制成冻干粉。记录稳定性和潜在的临床用途。4.开发和测定组织/血液生物标志物，作为BACPTDP吸收和疗效(药效学)的指标。5.为未来的第一阶段研究做好IND准备。完成这些研究后，将提交FDA IND文件。 公共卫生相关性：BACPTDP是一种新型喜树碱，最初由杜克大学设计，用于治疗低氧、血管稀少的具有酸性环境的肿瘤。在胰腺癌、结肠癌、卵巢癌和肺癌异种移植模型上进行的I期GRANT中进行的研究，并在此进行综述，支持我们推进该产品并为临床试验做好准备的决定。随后，Dekk-TEC与杜克大学三角研究所(RTI)合作，完成临床前开发，准备IND，并为产品的第一阶段临床试验做好准备。在后者之前，Dekk-TEC建议进行必要的临床前毒性、药代动力学、配方和稳定性研究。所描述的研究将满足将要设计的第一阶段研究的要求。

DESCRIPTION (provided by applicant): 7-Butyl-10-aminocamptothecin (BACPT), as a water-soluble dipeptide pro-drug - BACPTDP, is a novel camptothecin analog that has increased activity in hypoxic/acidic tumor tissues, characteristic of fast growing cancers that characteristically have deficient vasculature and outgrow their blood supply. Both in vitro and in vivo studies support the potential usefulness of BACPTDP in the treatment of pancreatic cancer. The significant responses seen with BACPTDP in the human PANC-1 xenograft model vs. other CPT controls are reviewed in support for the pre-clinical studies proposed in this application. The specific objectives of this Phase II study will be to: 1. Synthesize 7-butyl-10-aminocamptothecin dipeptide (BACPTDP) in 10-20 g quantities - sufficient for preclinical studies and formulation studies. 2. Conduct mouse and dog toxicity and pharmacokinetic studies. 3. Formulate the drug as a lyophilized powder. Document stability and potential clinical usefulness. 4. Develop and assay tissue/blood biomarkers as indicators for BACPTDP absorption and efficacy (pharmacodynamics). 5. Prepare the IND for future Phase I studies. Upon completion of these studies an FDA IND submission will be made. PUBLIC HEALTH RELEVANCE: BACPTDP is a novel camptothecins that was originally designed at Duke University to be used in the treatment of hypoxic, poorly vascularized tumors that possessed acidic environments. Studies conducted in the Phase I grant in pancreas, colon, ovarian and lung cancer xenograft models and reviewed herein, support our decision to move the product forward and ready it for clinical trials. Subsequently, DEKK-TEC has partnered with Duke and Research Triangle Institute (RTI) to complete the pre-clinical development, prepare the IND and ready the products for a Phase 1 clinical trial. Prior to the latter, DEKK-TEC proposes conducting the necessary pre- clinical toxicity, pharmacokinetic, formulation and stability studies. The studies as described will fulfill the requirements for a Phase I study to be designed.