Experimental Radiotherapy and Chemotherapy With a Potent New Hypoxic Cytotoxin

描述（由申请人提供）：本项目的总体目标是对新型高效缺氧细胞毒素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是我们的合作者，奥克兰大学的Denny和Wilson博士最近开发的一种二硝基苯甲酰胺多聚体（DNBM），其具有比目前缺氧细胞毒素替拉扎明（TPZ）原型更好的性质，包括大量的旁观者杀伤，使其对实体瘤中的需氧细胞和缺氧细胞具有活性。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药进入1期试验。将低氧细胞毒素与常规抗癌疗法组合的益处是基于以下事实：大多数人实体瘤具有低氧水平（低氧）的区域，并且这些区域中的细胞对辐射和许多化疗药物的杀伤具有抗性。TPZ与放疗和基于顺铂的化疗联合治疗已显示出相当大的临床获益。我们的初步研究表明，PR- 104与两种不同的人肿瘤异种移植物的分次辐射组合上级TPZ，并且具有显著的单药活性。我们将重点放在头颈部癌症，因为这是缺氧细胞毒素与放疗和化疗相结合的理想部位。将使用PR-104与TPZ平行的几种不同的人头颈部肿瘤异种移植物进行肿瘤疗效研究，以比较它们在许多不同情况下的相对疗效！我们的具体目的是1）确定通过彗星测定法测量的DNA链间交联是否可以用作PR-104活性的替代标记物，其可以用于临床，2）测定PR-104与分次照射组合在多种人头颈癌异种移植物中的功效，3）确定PR-104的活性依赖于肿瘤缺氧的程度，和4）确定PR-104增强用于头颈癌的最重要的抗癌药物的活性的程度。该项目直接适用于人类健康：其原理与TPZ相同，TPZ是第一种显示临床益处的缺氧细胞毒素，但可能大大上级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.