Copper-64-diacetyl-bis(N4-methylthiosemicarbazone):: An agent for radiotherapy
Copper-64-diacetyl-bis(N4-methylthiosemicarbazone):: An agent for radiotherapy
复制标题
DOI：
10.1073/pnas.98.3.1206
复制
发表时间：
2001-01-30
影响因子：
11.1
通讯作者：
Welch, MJ
中科院分区：
文献类型：
--
作者：
Lewis, JS;Laforest, R;Welch, MJ
缺氧选择性Cu-64-二乙酰基-双（N-4-甲基缩氨基硫脲）（Cu-64-ATSM）全身给药可显著延长荷人GW 39结肠癌仓鼠的存活时间。在携带7日龄（0.5-1.0 g）或15日龄（1.5-2.0 g）肿瘤的动物中进行放射治疗实验。研究比较了用0、4、6、7、8或10 mCi的Cu-64-ATSM（1 Ci = 37 CBq）单次剂量与或不与血管扩张剂肼苯哒嗪治疗的动物。还研究了间隔72小时的3 x 4 mCi多次给药方案。与对照组相比，>6 mCi的Cu-64-ATSM的单次剂量和剂量分级方案显著增加了仓鼠的存活时间。最高剂量，10 mCi的64 Cu-ATSM，在50%的携带7天大肿瘤的动物中将存活期增加到135天，比对照动物的存活期（20天）长6倍，仅出现短暂的白细胞减少症和血小板减少症，但没有明显的毒性。根据仓鼠生物分布计算人体吸收剂量;剂量关键器官为大肠下部（1.43 +/- 0.19 rad/mCi）和大肠上部（1.20 +/- 0.38 rad/mCi）。高分辨率MRI和正电子发射断层扫描使用10 mCi的治疗管理被用来监测肿瘤体积和形态，并准确地评估肿瘤剂量，给出肿瘤剂量为81 +/- 7.5 rad/mCi。Cu-64-ATSM能显著延长荷瘤动物的生存时间，且无急性毒性，是一种很有前途的放射治疗药物。
Systemic administration of hypoxia-selective Cu-64-diacetyl-bis(N-4-methylthiosemicarbazone) (Cu-64-ATSM) has increased significantly the survival time of hamsters bearing human GW39 colon cancer tumors. Radiotherapy experiments were performed in animals bearing either 7-day-old (0.5-1.0 g) or 15-day-old (1.5-2.0 g) tumors. Studies compared animals treated with a single dose of 0, 4, 6, 7, 8, or 10 mCi of Cu-64-ATSM (1 Ci = 37 CBq) with or without the vasodilator hydralazine. A multiple dose regimen of 3 x 4 mCi at 72-h intervals was studied also. Single doses of >6 mCi of Cu-64-ATSM and the dose-fractionation protocol significantly increased the survival time of the hamsters compared with controls. The highest dose, 10 mCi of 64Cu-ATSM, increased survival to 135 days in 50% of animals bearing 7-day-old tumors, 6-fold longer than control animals' survival (20 days), with only transient leucopenia and thrombocytopenia but no overt toxicity. Human absorbed doses were calculated from hamster biodistribution; the dose-critical organs were the lower large intestine (1.43 +/- 0.19 rad/mCi) and upper large intestine (1.20 +/- 0.38 rad/mCi). High-resolution MRI and positron-emission tomography using a therapeutic administration of 10 mCi were used to monitor tumor volume and morphology and to assess tumor dosimetry accurately, giving a tumor dose of 81 +/- 7.5 rad/mCi. Cu-64-ATSM has increased the survival time of tumor-bearing animals significantly with no acute toxicity and thus is a promising agent for radiotherapy.