Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis
Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis
复制标题
DOI：
10.1093/jnci/djk054
复制
发表时间：
2007-02-21
期刊：
影响因子：
--
通讯作者：
Clezardin, Philippe
中科院分区：
文献类型：
--
作者：
Daubine, Florence;Le Gall, Celine;Clezardin, Philippe
背景：在动物模型中，双膦酸盐表现出直接的抗肿瘤活性，但只有在高剂量时，才与临床批准用于治疗骨骼转移的癌症患者的给药方案不相容。我们比较了双磷酸盐唑来膦酸和氯膦酸临床给药方案对骨转移小鼠模型的抗肿瘤作用。方法小鼠（每组6 ~ 10只）分别在预防方案前、治疗方案后静脉注射人B02/GFP，分别给予唑来膦酸、氯膦酸或载药。2个乳腺癌细胞，表达绿色荧光蛋白（GFP）和荧光素酶并转移到骨。唑来膦酸分为每日、每周或单次给药，累积剂量为98-100 μ g/kg体重，相当于患者静脉给药4 mg。氯膦酸钠以每日剂量（530 μ g/kg/天）给予，相当于患者每日口服临床剂量1600 mg。骨破坏通过x线摄影、x线吸收仪或断层扫描和组织形态测量（作为骨体积与组织体积的比值）来测量。采用组织形态学（肿瘤负荷与软组织体积之比[TB/STV]）和荧光素酶活性测定骨骼肿瘤负荷。所有统计检验均为双侧检验。结果在治疗方案中，每日服用氯膦酸钠对降低TB/STV比率的效果不如每日服用氯膦酸钠(53% vs 87%，差异= 34%，95%可信区间[Cl] = 16% ~ 44%， P
Background Bisphosphonates exhibit direct antitumor activity in animal models, but only at high doses that are incompatible with the clinical dosing regimens approved for the treatment of cancer patients with skeletal metastases. We compared the antitumor effects of clinical dosing regimens of the bisphosphonates zoledronic acid and clodronate in a mouse model of bone metastasis.Methods Mice (n = 6-10 per group) were treated with zoledronic acid, clodronate, or vehicle starting before (preventive protocols) or after (treatment protocols) intravenous injection with human B02/GFP.2 breast cancer cells, which express green fluorescent protein (GFP) and luciferase and metastasize to bone. Zoledronic acid was given as daily, weekly, or single doses at a cumulative dose of 98-100 mu g/kg body weight, equivalent to the 4-mg intravenous dose given to patients. Clodronate was given as a daily dose (530 mu g/kg/day), equivalent to the daily 1600-mg oral clinical dose given to patients. Bone destruction was measured by radiography, x-ray absorptiometry or tomography, and histomorphometry (as the ratio of bone volume to tissue volume). Skeletal tumor burden was measured by histomorphometry (as the ratio of tumor burden to soft tissue volume [TB/STV]) and luciferase activity. All statistical tests were two-sided.Results In treatment protocols, daily clodronate was less effective at decreasing the TB/STV ratio than daily (53% versus 87%, difference = 34%, 95% confidence interval [Cl] = 16% to 44%, P