New Radiation-Activated Antitumor Agents That Target Hypoxia

描述(申请人提供)：癌症疗法杀死癌细胞，但对健康细胞的毒性仅略低。我们需要更多的选择性药物来专门杀死癌细胞。由于癌细胞分裂如此之快，它们经常处于缺氧(缺氧)状态。这种缺氧可以被用来专门针对要摧毁的癌细胞。这项研究的长期目标是开发毒性更低、更具选择性和更有效的新的低氧靶向抗癌药物。这一特殊应用的目的是设计和合成一系列新的辐射激活的抗肿瘤药物，这些药物包含双重有效的效应器和更有效的触发因素，并利用合成DNA和细胞DNA进行生物学研究。这些药物在正常组织中应该是无毒的，并且可以在肿瘤组织中发现的低氧条件下，在照射时被选择性地激活以释放多种有毒物种(效应物)。这些效应器被设计成形成有害的DNA损伤，如DNA链间交链(ICL)或DNA烷基化，可以阻止DNA复制或转录，并杀死肿瘤细胞。这项拟议的研究是基于我们最近发现的在低氧条件下芳甲基自由基形成DNA链间交联的基础上进行的。这项拟议研究的基本原理是，一旦开发出有效的触发因素和有效的效应器，新的药物将具有更高的选择性和更有效的抗癌药物候选药物，用于治疗侵袭性癌症。将开发合成方法来制备拟议的化合物。它们将通过固相DNA合成被结合成短寡核苷酸。将研究它们在交联键形成和DNA烷基化方面的DNA损伤特征和机理。通过检测低氧或好氧条件下的交联率来评估低氧特异性。最有希望的药物将在体外和体内用肿瘤细胞进行研究。此外，还将制备新的、有效的破坏DNA的官能团以及其他类似物。从这项研究中获得的知识将有助于解决有关DNA损伤和抗癌药物开发的基本问题，并将使包括有机化学、生物化学、药物化学、毒理学和细胞生物学在内的广泛学科受益。 公共卫生相关性：拟议的研究与公共健康相关，因为新的低氧靶向抗癌药物的开发有可能发现一类新的抗癌药物，用于治疗侵袭性癌症。所获得的知识将有助于解决有关DNA损伤和抗癌药物开发的基本问题。因此，拟议的研究与NIH使命的一部分相关，即追求有助于减轻人类疾病负担的基础知识。

DESCRIPTION (provided by applicant): Cancer therapies kill cancer cells, but are only marginally less toxic to healthy cells. We need more selective agents to specifically kill cancer cells. Since cancer cells divide so rapidly, they are very often hypoxic (oxygen-starved). This hypoxia can be used to specifically target cancer cells for destruction. The long-term goal of this research is to develop new hypoxia-targeting anticancer drugs that are less toxic, more selective, and more potent. The objective of this particular application is to design and synthesize a series of new radiation-activated antitumor agents that contain dual potent effectors and more efficient triggers, and to perform biological studies with both synthetic and cellular DNA. These agents should be non-toxic in normal tissue, and can be selectively activated to release multiple toxic species (effectors) upon irradiation under the hypoxic conditions found in tumor tissue. The effectors are designed to form deleterious DNA damage, such as DNA interstrand cross-links (ICLs) or DNA alkylations that can block DNA replication or transcription and kill tumor cells. The proposed research has been formulated on the basis of our recent discovery that the arylmethyl radicals form the DNA interstrand crosslinks under hypoxic condition. The rationale for the proposed research is that, once the efficient triggers and the potent effectors are developed, the new agents will be more selective and more potent anticancer drug candidates for the treatment of aggressive cancers. Synthetic methodologies will be developed to prepare the proposed compounds. They will be incorporated into short oligonucleotides via solid- phase DNA synthesis. Their DNA-damage profiles and mechanism with respect to cross-link formation and DNA alkylation will be studied. The hypoxia-specificity will be evaluated by examining cross-linking efficiency under hypoxic or aerobic conditions. The most promising agents will be pushed forward for in vitro and in vivo study with tumor cells. In addition, new, potent DNA- damaging functional groups will be prepared, as well as other analogs. The knowledge gained from this study will be useful for addressing fundamental questions concerning DNA damage and anticancer drug development and will benefit a broad range of disciplines, including organic chemistry, biochemistry, medicinal chemistry, toxicology, and cell biology. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the development of new hypoxia- targeting antitumor agents has the potential to identify a new class of anticancer drugs for the treatment of aggressive cancers. The knowledge acquired will be useful for addressing fundamental questions concerning DNA damage and anticancer drug development. Thus, the proposed research is relevant to the part of NIH's mission that is in pursuit of fundamental knowledge that will help to reduce the burdens of human illness.