Mechanistic and Translational Studies of PR-104:A New Hypoxia Activated Cytotoxin

这个项目的目标是以一种新的和高效的方式进行机械性和平移性研究 缺氧激活药物PR-104，特别是在评估其与放射治疗和 用吉西他滨。PR-104是我们的合作者最近发现的一种二硝基苯甲酰胺芥末(DNBM) 丹尼和威尔逊博士在目前的低氧细胞毒素原型的基础上进行了改进， 替拉帕明(TPZ)，包括大量的旁观者杀戮，使其具有抗需氧活性以及 实体瘤中的缺氧细胞。它于2006年1月进入第一阶段临床试验。将多个 低氧细胞毒素与传统的抗癌治疗是基于这样一个事实，即大多数人类实体瘤 有低氧水平的区域(缺氧)，这些区域的细胞对辐射具有抵抗力 还有许多化疗药物。TPZ已经显示出联合应用的临床益处。 放射治疗和顺铂为主的化疗。我们的初步研究表明，PR-104优于 TPZ联合分割放射治疗两种不同的人肿瘤移植瘤 大量的单一代理活动。我们将重点关注头颈部和胰腺癌，前者与 分次照射，后者使用吉西他滨。辐射对肿瘤疗效的研究将是 用PR-104与TPZ并行对不同类型的人头颈部肿瘤移植瘤进行治疗 比较它们的相对疗效，PR-104与吉西他滨联合使用的研究将是 采用异种胰腺移植作为皮下和原位模型。我们的具体目标是1) PR-104与TPZ增强头颈部分次照射的疗效比较 异种移植，2)通过DMA检测活性PR-104代谢物在肿瘤中的分布 用碱性彗星试验进行链间交联实验3)分析PR-2的药效及作用机制 104联合吉西他滨与胰腺肿瘤异种移植，4)以确定 无论有无照射，PR-104的活性都可以通过使用血管增加肿瘤缺氧来增加 靶向剂5)以确定使用NTR可提高PR-104活性的程度 表达产孢子杆菌，以及6)检验PR-104的G1毒性可以通过以下方法降低的假设 肠道菌群减少。这个项目对人类健康有直接的适用性：它的基本原理是 与TPZ相同，它是第一种显示临床益处的缺氧性细胞毒素，但PR-104似乎优于 因此，与TPZ相比，它具有更大程度提高癌症治愈率的潜力

The goal of this project is to perform mechanistic and translational studies with a new and highly effective hypoxia-activated drug, PR-104, particularly in evaluating its potential for combination with radiotherapy and with gemcitabine. PR-104 is a dinitrobenzamide mustards (DNBM), recently discovered by our collaborators Drs. Denny and Wilson, with improved properties over the current prototype of a hypoxic cytotoxin, tirapazamine (TPZ), including a substantial bystander killing that gives it activity against aerobic as well as hypoxic cells in solid tumors. It entered Phase 1 clinical trials in January 2006. The benefit of combining a hypoxic cytotoxin with conventional anticancer therapy is based on the fact that most human solid tumors have regions at low oxygen levels (hypoxia) and the cells in these regions are resistant to killing by radiation and many chemotherapeutic drugs. TPZ has already demonstrated clinical benefit in combination with radiotherapy and cisplatin based chemotherapy. Our preliminary studies show that PR-104 is superior to TPZ in combination with fractionated radiation with two different human tumor xenografts as well as having substantial single agent activity. We will focus on head and neck and pancreatic cancers, the former with fractionated radiation and the latter with gemcitabine. The tumor efficacy studies with radiation will be performed with different human head and neck tumor xenografts with PR-104 in parallel with TPZ in order to compare their relative efficacies, and the studies with PR-104 in combination with gemcitabine will be performed with pancreatic xenografts both as subcutaneous and orthotopic models. Our specific aims are 1) to compare the efficacy of PR-104 and TPZ in potentiating fractioned irradiation to head and neck xenografts, 2) to measure the distribution of active PR-104 metabolites in tumors by assaying DMA interstrand crosslinks by the alkaline comet assay 3) to assay the efficacy and mechanism of action of PR- 104 in combination with gemcitabine with pancreatic tumor xenografts, 4) to determine the extent to which the activity of PR-104 with or without irradiation can be increased by increasing tumor hypoxia using vascular targeting agents 5) to determine the extent to which the activity of PR-104 can be increased using NTR expressing C.sporogenes, and 6) to test the hypothesis that the Gl toxicity of PR-104 can be reduced by reduction of intestinal microflora. This project has direct applicability to human health: It's rationale is the same as that of TPZ, the first hypoxic cytotoxin to show clinical benefit, yet PR-104 appears to be superior to TPZ, and therefore has the potential of improving cancer cure rates to a greater extent than does TPZ