Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales , Sydney, New South Wales 2052, Australia.
Mol Pharm. 2013 Oct 7;10(10):3882-91. doi: 10.1021/mp4003464. Epub 2013 Sep 10.
The ability to assess in near-real time the tumor cell killing efficacy of chemotherapy regimens would improve patient treatment and survival. An ineffective regimen could be abandoned early in favor of a more effective treatment. We sought to noninvasively image treatment-related tumor cell death in mice using an optically labeled synthetic heat shock protein-90 (Hsp90) alkylator, 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid (GSAO). The Hsp90 chaperone is an important element in oncogene addiction and tumor cell survival, and its expression is enhanced by chemotherapy. These factors were predicted to favor the detection of tumor cell death using GSAO. GSAO specifically labeled apoptotic and necrotic tumor cells in culture and cells of comparable morphology in subcutaneous human pancreatic carcinoma tumors in mice. A near-infrared fluorescent conjugate of GSAO was used to noninvasively image cyclophosphamide-induced tumor cell death in murine orthotopic human mammary tumors. The GSAO conjugate did not accumulate in healthy organs or tissues in the mouse, and unbound compound was excreted rapidly via the kidneys. There was a significant increase in the GSAO fluorescence signal in the treated tumors measured either in vivo or ex vivo, and the fluorescence signal colocalized with apoptotic cells in sectioned tumors. The favorable biodistribution of optically labeled GSAO, the nature of its tumor cell target, and its capacity to noninvasively detect tumor cell death should facilitate the application of this compound in studies of the efficacy of existing and new chemotherapeutics.
能够近乎实时地评估化疗方案对肿瘤细胞杀伤效果，将改善患者的治疗效果和生存情况。一种无效的方案可以被早期放弃，转而采用更有效的治疗方法。我们试图使用光学标记的合成热休克蛋白 90（Hsp90）烷化剂 4-（N-（S-谷胱甘肽乙酰基）氨基）苯砷酸（GSAO），非侵入性地对小鼠的治疗相关肿瘤细胞死亡进行成像。Hsp90 伴侣是致癌基因成瘾和肿瘤细胞存活的重要因素，其表达会被化疗增强。这些因素预计会有利于使用 GSAO 检测肿瘤细胞死亡。GSAO 可特异性标记体外培养的凋亡和坏死肿瘤细胞，以及在小鼠皮下人胰腺癌细胞肿瘤中具有相似形态的细胞。GSAO 的近红外荧光共轭物用于非侵入性地对小鼠原位人乳腺肿瘤中的环磷酰胺诱导的肿瘤细胞死亡进行成像。GSAO 共轭物不会在小鼠的健康器官或组织中积累，未结合的化合物会通过肾脏迅速排出。在治疗的肿瘤中，无论是体内还是离体测量，GSAO 荧光信号都显著增加，并且荧光信号与切片肿瘤中的凋亡细胞共定位。光学标记的 GSAO 具有良好的生物分布、其肿瘤细胞靶标性质以及非侵入性检测肿瘤细胞死亡的能力，这应有助于该化合物在现有和新型化疗药物疗效研究中的应用。
