Wilson W R, Li A E, Cowan D S, Siim B G
Department of Pathology, The University of Auckland, New Zealand.
Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):905-8. doi: 10.1016/s0360-3016(98)00358-7.
5,6-dimethylxanthenone-4-acetic acid (DMXAA) selectively damages tumor vasculature and is currently in clinical trial as an antitumor agent. Its ability to induce synthesis of tumor necrosis factor (TNF), and its apparent selectivity for poorly-perfused regions in tumors, suggests it possible use in combination with radiotherapy. This investigation examines activity of DMXAA as a radiation modifier using two murine tumors.
Tumor growth delay was evaluated using i.m. RIF-1 and MDAH-MCa-4 tumors irradiated in unanaesthetised, restrained mice (cobalt-60) using single dose or multiple fractions (8 x 2.5 Gy over 4 days) with DMXAA administered i.p. at various times in relation to irradiation.
Administration of DMXAA (80 micromol/kg, i.p.) immediately after radiation resulted in a large increase in tumor growth delay, giving a radiation dose modifying factor of 2.3 for RIF-1 and 3.9 for MDAH-MCa-4. The combination was less active when radiation was given 1-4 h after DMXAA, but was highly active 12-48 h after DMXAA. At the latter times, clamping the tumor blood supply caused a large increase in radioresistance. These studies suggest that cells surviving DMXAA are hypoxic for only a short period. DMXAA increased overall growth delay when administered daily during fractionated irradiation, giving an approximately additive response.
The marked synergy between DMXAA and single dose ionising radiation may reflect the complementarity of these agents at the microregional level, with DMXAA preferentially killing hypoxic cells in poorly perfused regions. Despite additional hypoxia shortly after DMXAA treatment, surviving cells appear to reoxygenate quickly which makes it feasible to use DMXAA before and during fractionated radiotherapy. The combination of fractionated radiation and DMXAA appears to be less effective than for single dose radiation (possibly because of the smaller contribution of hypoxia under these conditions), but may be therapeutically useful.
5,6 - 二甲基呫吨酮 - 4 - 乙酸（DMXAA）可选择性地损伤肿瘤血管，目前作为一种抗肿瘤药物正处于临床试验阶段。它诱导肿瘤坏死因子（TNF）合成的能力，以及其对肿瘤中灌注不良区域的明显选择性，提示其有可能与放射治疗联合使用。本研究使用两种小鼠肿瘤模型来检测DMXAA作为辐射修饰剂的活性。
在未麻醉、受限的小鼠（钴 - 60）中，通过腹腔注射DMXAA并在与照射相关的不同时间点，使用单次剂量或多次分割剂量（4天内8×2.5 Gy）照射肌肉注射的RIF - 1和MDAH - MCa - 4肿瘤，评估肿瘤生长延迟情况。
放疗后立即腹腔注射DMXAA（80微摩尔/千克）可使肿瘤生长延迟大幅增加，RIF - 1的辐射剂量修饰因子为2.3，MDAH - MCa - 4为3.9。当在DMXAA给药后1 - 4小时进行放疗时，联合治疗的活性较低，但在DMXAA给药后12 - 48小时活性较高。在后者时间段，钳夹肿瘤供血会导致放射抗性大幅增加。这些研究表明，经DMXAA处理后存活的细胞仅在短时间内处于缺氧状态。在分割照射期间每日给予DMXAA可增加总体生长延迟，呈现近似相加的反应。
DMXAA与单次剂量电离辐射之间显著的协同作用可能反映了这些药物在微观区域水平上的互补性，DMXAA优先杀死灌注不良区域的缺氧细胞。尽管在DMXAA治疗后不久会出现额外的缺氧情况，但存活细胞似乎能迅速再氧合，这使得在分割放疗前及放疗期间使用DMXAA成为可能。分割放疗与DMXAA联合使用似乎不如单次剂量放疗有效（可能是因为在这些条件下缺氧的作用较小），但可能具有治疗价值。
