Gandara David R, Lara Primo N, Goldberg Zelanna, Le Quynh T, Mack Phillip C, Lau Derick H M, Gumerlock Paul H
Division of Hematology-Oncology and the Department of Radiation Oncology, University of California, Sacramento, CA 95817, USA.
Semin Oncol. 2002 Feb;29(1 Suppl 4):102-9. doi: 10.1053/sonc.2002.31531.
Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and metastasis, and markedly reducing the efficacy of both radiotherapy and chemotherapy. Similarly, clinical studies measuring pretreatment tumor oxygen status confirm that the presence of hypoxia confers a negative impact on local control, disease-free survival, and overall survival. Despite these data and extensive past research efforts, the promise of developing selective hypoxic-cell sensitizers has been largely unfulfilled. In contrast, tirapazamine is the rationally designed prototype for a new class of therapeutic agents targeting tumor hypoxia: hypoxic cytotoxins. Tirapazamine is bioreductively activated in hypoxic cells and has been shown to potentiate the cytotoxicity of radiation and a number of chemotherapeutic drug classes, in particular platinum compounds and taxanes. This article reviews the preclinical and clinical development of tirapazamine, as well as current trials in non-small cell lung cancer designed to provide proof of principle for this new category of cancer therapeutics.
体内和体外的临床前模型表明，肿瘤缺氧会改变恶性细胞表型，促使p53突变，刺激血管生成和转移，并显著降低放疗和化疗的疗效。同样，测量治疗前肿瘤氧状态的临床研究证实，缺氧的存在会对局部控制、无病生存期和总生存期产生负面影响。尽管有这些数据以及过去广泛的研究努力，但开发选择性低氧细胞增敏剂的前景在很大程度上仍未实现。相比之下，替拉扎明是一种合理设计的新型治疗药物的原型，这类药物靶向肿瘤缺氧：低氧细胞毒素。替拉扎明在缺氧细胞中通过生物还原被激活，并且已被证明可增强辐射和多种化疗药物（特别是铂类化合物和紫杉烷类）的细胞毒性。本文综述了替拉扎明的临床前和临床开发情况，以及目前在非小细胞肺癌中进行的试验，这些试验旨在为这类新型癌症治疗药物提供原理验证。
