Experimental Radiotherapy and Chemotherapy With a Potent New Hypoxic Cytotoxin

描述（由申请人提供）：该项目的总体目标是对一种新的高效缺氧细胞毒素PR-104进行转化研究，特别是评估其与放疗和化疗联合使用的潜力。PR-104是一种二硝基苯甲酰胺芥菜（DNBM），最近由我们的合作者dr。Denny和Wilson在奥克兰大学（University of Auckland）的研究中发现，这种药物的性能比目前的低氧细胞毒素替拉帕嗪（TPZ）的原型有所改进，包括对实体肿瘤中的有氧细胞和缺氧细胞具有实质性的杀伤作用。预计将于2005年12月/ 2006年1月在美国、澳大利亚和新西兰作为单一药物进入一期临床试验。将低氧细胞毒素与常规抗癌疗法相结合的好处是基于这样一个事实，即大多数人类实体肿瘤都有低氧水平（缺氧）的区域，而这些区域的细胞对辐射和许多化疗药物的杀伤具有抵抗力。TPZ与放疗和以顺铂为基础的化疗联合使用已显示出相当大的临床益处。我们的初步研究表明，PR- 104在两种不同的人类肿瘤异种移植物的分次放射治疗中优于TPZ，并且具有良好的单剂活性。我们将重点关注头颈部癌症，因为这是将缺氧细胞毒素与放疗和化疗相结合的理想部位。肿瘤疗效研究将在几种不同的人类头颈部肿瘤异种移植物中进行，与PR-104和TPZ并行，以比较它们在许多不同情况下的相对疗效！我们的具体目标是：1)确定彗星实验测量的DNA链间交联是否可以作为PR-104活性的替代标记物，用于临床；2)测定PR-104与分次照射在各种人类头颈癌异种移植物中的疗效；3)确定PR-104活性对肿瘤缺氧的依赖程度。4)确定PR-104在多大程度上增强了头颈癌中最重要的抗癌药物的活性。该项目直接适用于人类健康：其原理与TPZ相同，TPZ是第一个显示临床益处的低氧细胞毒素，但可能大大优于TPZ，因此具有比TPZ更大程度提高人类癌症治愈率的强大潜力。

DESCRIPTION (provided by applicant): The overall goal of this project is to perform translational studies with a new and highly effective hypoxic cytotoxin, PR-104, particularly in evaluating its potential for combination with radiotherapy and chemotherapy. PR-104 is a dinitrobenzamide mustards (DNBM) recently developed by our collaborators, Drs. Denny and Wilson at the University of Auckland, which has 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 is expected to enter Phase 1 trials as a single agent in the US, Australia and New Zealand in December 2005/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 considerable 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 cancer, as this is the ideal site for combining a hypoxic cytotoxin with radiotherapy and chemotherapy. The tumor efficacy studies will be performed with several different human head and neck tumor xenografts with PR-104 in parallel with TPZ in order to compare their relative efficacies in a number of different situations! Our specific aims are 1) to determine whether DNA interstrand crosslinks measured by the comet assay can be used as a surrogate marker for activity of PR-104 that could be used in the clinic, 2) to assay the efficacy of PR-104 in combination with fractionated irradiation in a variety of human head and neck cancer xenografts, 3) to determine the extent to which the activity of PR-104 depends on tumor hypoxia, and 4) to determine the extent to which PR-104 potentiates the activity of the most important anticancer drugs used in head and neck cancer. This project has direct applicability to human health: its rationale is the same as that of TPZ, the first hypoxic cytotoxin to show clinical benefit, yet could be substantially superior to TPZ, and therefore has the strong potential of improving human cancer cure rates to a greater extent than does TPZ.