Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents.
Effect of clinical levels of misonidazole on the response of tumour and normal tissues in the mouse to alkylating agents.
复制标题
米索硝唑临床水平对小鼠肿瘤和正常组织对烷化剂反应的影响。
DOI：
10.1038/bjc.1982.111
复制
发表时间：
1982
影响因子：
8.8
通讯作者：
Hirst,DG
中科院分区：
文献类型：
--
作者：
Brown,JM;Hirst,DG
进行实验以确定在小鼠肿瘤中大剂量的米索咪唑（MISO）后观察到的烷化剂细胞毒性的增强是否也可以通过长期暴露于与临床上可以耐受的水平相似的低MISO水平来实现。每1/2 h注射一次小剂量MISO，可使小鼠血浆中的浓度维持在约100 μ g/ml，持续7 h。使用再生长延迟和细胞存活克隆测定，在RIF-1肿瘤中研究了这种治疗与环磷酰胺（CY）或美法仑（L-PAM）组合的效果。在每种情况下，长期暴露于低水平的MISO得到的增强比非常接近于大剂量的单次剂量。在使用的烷化剂剂量范围内，CY获得的ER为1.6-2.0，L-PAM获得的ER为1.8-2.2。在CY实验中，还研究了2个正常组织系统（骨髓和WBC计数）的反应。在这两种情况下，CY损伤没有显著增强。在L-PAM实验中，将LD 50/30和WBC计数确定为正常组织终点。多次MISO没有效果。我们的研究结果表明，MISO的水平，可以达到安全的人产生良好的增强肿瘤细胞毒性的2种广泛使用的化疗药物，而不增加对正常组织的损害。
Experiments were carried out to determine whether the enhancement of alkylating-agent cytotoxicity seen after large single doses of misonidazole (MISO) in mouse tumours can also be achieved by prolonged exposure to low MISO levels similar to those which can be tolerated clinically. The level in mouse blood plasma could be maintained at about 100 micrograms/ml for 7 h by injecting small doses of MISO every 1/2 h. The effect of this treatment in combination with cyclophosphamide (CY) or melphalan (L-PAM) was studied in the RIF-1 tumour, using regrowth delay and cell-survival cloning assays. In each case, prolonged exposure to low levels of MISO gave enhancement ratios very close to those obtained with a large single dose. ERs of 1.6-2.0 were obtained with CY and 1.8-2.2 with L-PAM over the range of alkylating-agent doses used. In experiments with CY the response of 2 normal-tissue systems, marrow and WBC count, was also studied. No significant enhancement of CY damage occurred in either case. In the L-PAM experiments the LD50/30 and WBC counts were determined as normal-tissue end points. Multiple MISO had no effect. Our results show that levels of MISO which can be achieved safely in man yield good enhancement of the tumour cytotoxicity of 2 widely used chemotherapeutic agents without increasing the damage to normal tissues.