Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide.
Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide.
复制标题
硝基咪唑缺氧细胞增敏剂 SR2508（依他硝唑）与环磷酰胺联合的 I 期/药代动力学/生化研究。
DOI：
10.1038/bjc.1993.424
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发表时间：
1993
影响因子：
8.8
通讯作者：
Comis,RL
中科院分区：
文献类型：
--
作者：
O'Dwyer,PJ;LaCreta,FP;Walczak,J;Cox,T;Litwin,S;Hoffman,JP;Zimny,M;Comis,RL
SR 2508在体外和体内使某些缺氧肿瘤细胞对放射和烷化剂的细胞毒性作用敏感。致敏的机制可能部分来自谷胱甘肽（GSH）的消耗，并可能抑制靶细胞中的GSH依赖性酶。我们用环磷酰胺750-1000 mg m-2治疗46例可评价患者，然后用SR 2508治疗8个剂量水平，范围从2.5至15.0 g m-2。每例患者最初接受SR 2508单药治疗，一周后接受环磷酰胺和SR 2508联合治疗。最初，骨髓抑制是主要毒性; SR 2508增强环磷酰胺诱导的白细胞减少症，需要在SR 2508剂量高于7.2 g m-2时将环磷酰胺剂量降低至750 mg m-2。在9.4 g/m-2以上的剂量下，观察到持续12-24 h的四肢肌肉疼痛和疼痛性感觉异常急性综合征的严重程度增加。在15.0 g/m-2剂量下治疗的三名患者中，有两名患者的这种副作用无法耐受。唯一的其他可重复的副作用是恶心和呕吐，这是可控的止吐药。采用HPLC法测定45例患者的血浆和尿液SR 2508浓度。血浆消除曲线符合二室模型。各剂量水平下的平均终末半衰期范围为5.1-5.8 h。平均血药浓度-时间曲线下面积与剂量呈线性相关，平均全身清除率范围为46.6-94.0 ml-1 min-1 m-2;肾脏清除率占65.7- 79.3%。环磷酰胺预处理不影响个体患者中SR 2508的动力学。外周血单个核细胞和肿瘤样本的谷胱甘肽含量的检查表明，在大多数患者中发生的耗竭低于50%的控制。GSH转移酶抑制发生在类似的时间过程中，但程度较低。这些数据表明，应在环磷酰胺给药前使用SR 2508对该方案进行进一步评价，并且有必要在环磷酰胺敏感性肿瘤中进行评价。
SR2508 sensitises certain hypoxic tumor cells in vitro and in vivo to the cytotoxic action of radiation and alkylating agents. The mechanism of sensitisation may derive in part from depletion of glutathione (GSH) and possibly inhibition of GSH-dependent enzymes in target cells. We treated 46 evaluable patients with cyclophosphamide 750-1000 mg m-2 followed by SR2508 at eight dose levels ranging from 2.5 to 15.0 g m-2. Each patient received SR2508 as a single agent initially, followed a week later by the combination of cyclophosphamide and SR2508. Initially, myelosuppression was the major toxicity; potentiation of cyclophosphamide-induced leukopenia by SR2508 required a dose reduction of cyclophosphamide to 750 mg m-2 at SR2508 doses above 7.2 g m-2. At doses above 9.4 g m-2 an acute syndrome of muscle pains and painful paresthesias of the extremities lasting 12-24 h was observed to occur with increasing severity. This side-effect was intolerable in two of three patients treated at 15.0 g m-2. The only other reproducible side-effect was nausea and vomiting which was controllable with antiemetics. Plasma and urine SR2508 concentrations were measured by HPLC in 45 patients. Plasma elimination curves fit a 2-compartment model. The mean terminal half-life at each dose level ranged from 5.1-5.8 h. The mean area under the plasma concentration-time curve was linearly related to dose, and mean total body clearance ranged from 46.6-94.0 ml-1 min-1 m-2; renal clearance accounted for 65.7-79.3%. Pretreatment with cyclophosphamide did not influence the kinetics of SR2508 in individual patients. Examination of the glutathione content of peripheral mononuclear cells and tumour samples showed that depletion to below 50% of control occurred in the majority of patients. GSH transferase inhibition occurred with a similar time-course, but to a lesser extent. These data suggest that the further evaluation of this regimen should be conducted with SR2508 administration preceding that of cyclophosphamide and that its evaluation in cyclophosphamide-sensitive tumours is warranted.
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DOI：
10.1098/rspb.1933.0044
发表时间：
1933-07-01
期刊：
PROCEEDINGS OF THE ROYAL SOCIETY OF LONDON SERIES B-CONTAINING PAPERS OF A BIOLOGICAL CHARACTER
影响因子：
--
作者：
Crabtree, HG;Cramer, W
通讯作者：
Cramer, W
Misonidazole和环磷酰胺对体内C3H乳腺癌中有氧细胞和低氧细胞的细胞毒性作用。
影响因子：
8.8
作者：
Grau C;Bentzen SM;Overgaard J
通讯作者：
Overgaard J
米索硝唑预处理增强马法兰交联的机制。
DOI：
10.1016/0360-3016(84)90511-x
发表时间：
1984
期刊：
International journal of radiation oncology, biology, physics
影响因子：
--
作者：
Taylor,YC;Sawyer,JM;Hsu,B;Brown,JM
通讯作者：
Brown,JM
米索硝唑和马来酸二乙酯在体内小鼠纤维肉瘤肿瘤中增强氮芥的 DNA 交联活性。
影响因子：
11.2
作者：
Murray,D;Meyn,RE
通讯作者：
Meyn,RE
与缺氧细胞敏化剂体外预孵育效应相关的因素及其在化学增敏中的可能影响。
影响因子：
3.4
作者：
Roizin-Towle,L;Biaglow,JE;Meltzer,HL;Varnes,ME
通讯作者：
Varnes,ME