COMBINING BIOREDUCTIVE DRUGS (SR-4233 OR SN-23862) WITH THE VASOACTIVE AGENTS FLAVONE ACETIC-ACID OR 5,6-DIMETHYLXANTHENONE ACETIC-ACID
COMBINING BIOREDUCTIVE DRUGS (SR-4233 OR SN-23862) WITH THE VASOACTIVE AGENTS FLAVONE ACETIC-ACID OR 5,6-DIMETHYLXANTHENONE ACETIC-ACID
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DOI：
10.1016/0360-3016(94)90292-5
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发表时间：
1994-05-15
影响因子：
7
通讯作者：
WILSON, WR
中科院分区：
文献类型：
--
作者：
CLIFFE, S;TAYLOR, ML;WILSON, WR
目的：为了确定黄酮乙酸（FAA）的有效类似物5，6-二甲基咕吨酮乙酸（DMXAA）是否抑制小鼠乳腺肿瘤中的血流，并评估DMXAA是否增强替拉扎明（SR 4233）和新型生物还原药物SN 23862（二硝基苯芥）的抗肿瘤作用。在C3 H/HeN小鼠的腿中。肿瘤血流量进行了评估，通过高锝酸盐清除方法和随后的生长延迟被确定在相同tumors.Results：DMXAA（65-70 μ mol/kg）的管理导致抑制肿瘤血流量约25%的控制值，没有恢复观察到36小时后治疗。DMXAA与SR 4233的组合相对于任一单独药物提供了肿瘤生长抑制的显著增加。在这种效果中，DMXAA在性质上与FAA相似，但效力约为FAA的10倍。DMXAA（65 μ mol/kg）和SR 4233（200 μ mol/kg）之间的相互作用最大，SR 4233在DMXAA前15分钟和DMXAA后60分钟之间给药。对于SN 23862，与DMXAA联合使用时观察到类似的生长延迟增强，DMXAA前15 min和DMXAA后4 h之间无明显的时间依赖性。当SR 4233（200 μ mole/kg）单独和与DMXAA（65-90 μ mole/kg）组合处理的组的平均值进行比较时，观察到肿瘤血流抑制和随后的生长延迟之间的相关性。这种血管活性药物与生物还原剂的组合导致增强的抗肿瘤作用。对于SR 4233和DMXAA，这种增强的作用可以通过在药物施用后不久测量肿瘤血流抑制来预测。
Purpose: To determine whether 5,6-dimethylxanthenone acetic acid (DMXAA), a potent analogue of flavone acetic acid (FAA) inhibits blood flow in mouse mammary tumors, and to assess whether DMXAA enhances the antitumor effects of Tirapazamine (SR 4233) and the novel bioreductive drug SN 23862 (a dinitrobenbenzene mustard).Methods and Material: MDAH-MCa-4 mouse mammary tumors were grown i.m. in the leg of C3H/HeN mice. Tumor blood flow was assessed by the pertechnetate clearance method and subsequent growth delay was determined in the same tumors.Results: Administration of DMXAA (65-70 mu mol/kg) resulted in inhibition of tumor blood flow to approximately 25% of control values, with no recovery observed up to 36 h post-treatment. Combination of DMXAA with SR 4233 provided a significant increase in tumor growth inhibition relative to either drug alone. In this effect, DMXAA was qualitatively similar to FAA, but was approximately 10 X more potent. The interaction between DMXAA (65 mu mol/kg) and SR 4233 (200 mu mol/kg) was maximal with SR 4233 given between 15 min before and 60 min after DMXAA. For SN 23862, a similar enhanced growth delay was observed in combination with DMXAA, with no obvious time dependence between 15 min before and 4 h after DMXAA. When mean values for groups treated with SR 4233 (200 mu mole/kg) alone and in combination with DMXAA (65-90 mu mole/kg) were compared, a correlation was observed between tumor blood flow inhibition and subsequent growth delay.Conclusion: DMXAA is a potent inhibitor of blood flow in MDAH-MCa-4 tumors. Combination of this vasoactive drug with bioreductive agents leads to an enhanced antitumor effect. For SR 4233 and DMXAA, this enhanced effect may be predictable by measurement of tumor blood flow inhibition shortly after drug administration.