Huxham Lynsey A, Kyle Alastair H, Baker Jennifer H E, McNicol Krista L, Minchinton Andrew I
Medical Biophysics Department, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Radiother Oncol. 2006 Feb;78(2):138-45. doi: 10.1016/j.radonc.2006.01.002. Epub 2006 Feb 7.
Tirapazamine is a hypoxic cytotoxin currently undergoing Phase II/III clinical evaluation in combination with radiation and chemotherapeutics for the treatment of non-hematological cancers. Tissue penetration studies using multicellular models have suggested that tirapazamine exposure may be limited to cells close to blood vessels. However, animal studies show tirapazamine enhances the anti-tumour activity of radiation and chemotherapy and clinical studies with tirapazamine, so far, are promising. To investigate this apparent paradox we examined the microregional effects of tirapazamine in vivo by mapping drug effects with respect to the position of blood vessels in tumour cryosections.
Tirapazamine was administered i.p. to mice bearing HCT-116 tumours, which were excised at various times after treatment. Images of multiple-stained cryosections were overlaid to provide microregional information on the relative position of proliferating cells, hypoxia, perfusion and vasculature.
We observed extensive and permanent vascular dysfunction in a large proportion of tumours from mice treated with tirapazamine. In the affected tumours, blood flow ceased in the centrally located tumour vessels, leaving a rim of functional vessels around the periphery of the tumour. This vascular dysfunction commenced within 24 h after tirapazamine administration and the areas affected appeared to be replaced by necrosis over the following 24-48 h.
Because the majority of hypoxic cells are located in the center of tumours we propose that the activity of tirapazamine in vivo may be related to its effects on tumour vasculature and that its activity against hypoxic cells located distal to functional blood vessels may not be as important as previously believed.
替拉扎明是一种低氧细胞毒素，目前正与放疗及化疗联合进行II/III期临床评估，用于治疗非血液系统癌症。使用多细胞模型进行的组织渗透研究表明，替拉扎明的暴露可能仅限于靠近血管的细胞。然而，动物研究显示替拉扎明可增强放疗和化疗的抗肿瘤活性，且迄今为止替拉扎明的临床研究前景良好。为研究这一明显的矛盾现象，我们通过在肿瘤冷冻切片中根据血管位置绘制药物效应图，来研究替拉扎明在体内的微区域效应。
给荷HCT-116肿瘤的小鼠腹腔注射替拉扎明，并在治疗后的不同时间切除肿瘤。将多次染色冷冻切片的图像叠加，以提供关于增殖细胞、低氧、灌注和脉管系统相对位置的微区域信息。
我们观察到在用替拉扎明治疗的小鼠的大部分肿瘤中存在广泛且持久的血管功能障碍。在受影响的肿瘤中，位于肿瘤中心的血管血流停止，仅在肿瘤周边留下一圈功能正常的血管。这种血管功能障碍在替拉扎明给药后24小时内开始，在接下来的24 - 48小时内，受影响的区域似乎被坏死组织取代。
由于大多数低氧细胞位于肿瘤中心，我们推测替拉扎明在体内的活性可能与其对肿瘤脉管系统的作用有关，并且其对位于功能性血管远端的低氧细胞的活性可能并不像之前认为的那么重要。
