Experimental Radiotherapy and Chemotherapy With a Potent New Hypoxic Cytotoxin

描述(申请人提供)：该项目的总体目标是对一种新的、高效的低氧细胞毒素PR-104进行转化研究，特别是在评估其与放射和化疗相结合的潜力方面。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芥末(DNBM)，它比目前的缺氧细胞毒素替拉帕明(TPZ)的原型有了改进的性质，包括大量的旁观者杀伤，使其对实体肿瘤中的需氧细胞和缺氧细胞具有活性。预计它将于2005年12月/2006年1月作为单一药物在美国、澳大利亚和新西兰进入第一阶段试验。将低氧细胞毒素与传统抗癌治疗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区域(低氧)，并且这些区域的细胞对辐射和许多化疗药物具有抵抗力。与放疗和顺铂为主的化疗相结合，TPZ已经显示出相当大的临床益处。我们的初步研究表明，PR-104在与两种不同的人肿瘤移植瘤的分割放射相结合时优于TPZ，并且具有显著的单剂活性。我们将重点放在头颈部癌症上，因为这是将缺氧细胞毒素与放射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头颈部肿瘤移植瘤中进行，PR-104与TPZ平行进行，以比较它们在多种不同情况下的相对疗效！我们的具体目标是：1)确定用彗星试验测量的DNA链间交联度是否可以用作PR-104活性的替代标记物，并用于临床；2)检测PR-104联合分次照射对各种头颈癌移植瘤的疗效；3)确定PR-104的活性在多大程度上依赖于肿瘤的缺氧；以及4)确定PR-104增强头颈癌治疗中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，但可能显著优于TPZ，因此具有在更大程度上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.