Therapeutic index by combination of adriamycin and docetaxel depends on dosing time in mice
Therapeutic index by combination of adriamycin and docetaxel depends on dosing time in mice
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DOI：
10.1158/0008-5472.can-05-1161
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Ohdo, S
中科院分区：
文献类型：
--
作者：
Tabuchi, M;To, H;Ohdo, S
尽管阿霉素和多西他赛联合治疗转移性乳腺癌显示出更好的治愈率，但严重的骨髓抑制和心脏毒性是剂量限制因素。本研究的目的是建立一个合适的给药方案，根据时间药理学方法，以减轻严重的不良反应。在实验1中，在光发作（HALO）后2、6、10、14、18或22小时腹膜内注射阿霉素或多西他赛，以估计毒性。在实验2中，评估了阿霉素和多西他赛联合给药的毒性和药代动力学的给药时间依赖性。此外，在未处理的小鼠中测定了髓细胞中的G（2）-M期。阿霉素引起的不良反应在2 HALO时最严重，在14 HALO时最好。另一方面，紫杉醇诱导的不良反应在14 HALO时比2 HALO时更严重。在联合研究中，D（2）-A（14）组（多西他赛在2 HALO给药，随后阿霉素在14 HALO给药）显示所有治疗组中毒性缓解最多。在药代动力学研究中，毒性的给药时间依赖性与阿霉素和多西他赛药代动力学的日变化无关。在未处理小鼠的骨髓细胞中发现了显著的G（2）-M期分布的24小时节律。多西他赛引起的白细胞减少的日变化与G（2）-M期分布的24小时节律相一致。这些结果表明，联合化疗的治疗指数可以通过在每种药物的最大不良反应缓解时给予阿霉素和多西他赛来提高。
Although the combination of adriamycin and docetaxel showed a better cure rate against metastatic breast cancer, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule, based on a chronopharmacologic approach, to relieve severe adverse effects. In experiment 1, adriamycin or docetaxel was injected i.p. at 2, 6, 10, 14, 18, or 22 hours after light onset (HALO) to estimate toxicities. In experiment 2, the dosing time dependency of toxicity and pharmacokinetics were assessed in the combination of adriamycin and docetaxel. In addition, G(2)-M phase in myelocyte cells was determined in nontreated mice. Adverse effects caused by adriamycin were shown to be the worst at 2 HALO and the best at 14 HALO. On the other hand, docetaxel-induced adverse effects were more severe at 14 HALO than at 2 HALO. In the combination study, the D(2)-A(14) group, in which docetaxel was administered at 2 HALO followed by adriamycin at 14 HALO, showed the most toxicity relief of all the treated groups. In the pharmacokinetic study, the dosing time dependency of toxicities was not related to the daily variation of pharmacokinetics of adriamycin and docetaxel. A significant 24-hour rhythm of G(2)-M phase distribution was found in myelocyte cells of nontreated mice. The daily variation of leukopenia caused by docetaxel corresponded to the 24-hour rhythm of G(2)-M phase distribution. These findings reveal that the therapeutic index of the combined chemotherapy can be improved by administering adriamycin and docetaxel at the time when the most adverse effects are relieved in each drug.