Influence of dosing schedule on toxicity and antitumor effects of a combination of adriamycin and docetaxel in mice
Influence of dosing schedule on toxicity and antitumor effects of a combination of adriamycin and docetaxel in mice
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DOI：
10.1158/1078-0432.ccr-1000-03
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发表时间：
2004-01-15
影响因子：
11.5
通讯作者：
Ohdo, S
中科院分区：
文献类型：
--
作者：
To, H;Shin, M;Ohdo, S
目的：虽然阿霉素（ADR）和多西紫杉醇（DOC）的联合治疗在临床研究中显示出更好的治疗转移性乳腺癌的治愈率，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最合适的给药方案，以缓解严重不良反应，提高抗肿瘤效果。 实验设计：同时给药组（ADR/DOC）同时给药ADR和DOC，而间歇给药组（ADR-DOC和DOC-ADR）则在第一种药物后12小时给药第二种药物。测量白细胞计数和存活率以估计不良反应。给药后，测定血液、骨髓细胞和心脏中的 ADR 和 DOC 浓度。为了阐明抗肿瘤作用，在开始注射药物后测量了荷有艾氏细胞的小鼠的肿瘤生长。结果：与盐水治疗组相比，同时给药组显示出严重的白细胞减少症。然而，间歇给药组的毒性有所降低。 DOC-ADR 组在给药组中表现出最佳的存活率。在药代动力学研究中，同时给药组的血浆、粒细胞和心脏中的ADR和DOC浓度显着高于间歇给药组。这些结果表明药代动力学相互作用可能导致同时服用 ADR 和 DOC 引起的白细胞减少症的变化。 DOC-ADR组的抗肿瘤效果在各给药组中最高。 结论：在本研究中，研究结果表明，与同时给药（ADR/DOC）组相比，DOC注射12小时后给予ADR（DOC-ADR组）不仅能更强地抑制肿瘤生长，而且能显着降低白细胞减少症，并与其他组相比显着减少中毒性死亡人数。
Purpose: Although the combination of Adriamycin (ADR) and docetaxel (DOC) showed a better cure rate against metastatic breast cancer in a clinical study, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve the antitumor effects.Experimental Design: Both ADR and DOC were administered simultaneously in the simultaneous-dosing group (ADR/DOC), whereas in the intermittent-dosing groups (ADR-DOC and DOC-ADR), the second drug was administered 12 h after the first drug. Leukocyte counts and survival were measured to estimate adverse effects. After administration, ADR and DOC concentrations in blood, myelocyte cells, and heart were determined. To clarify the antitumor effect, tumor growth was measured in Ehrlich-cell-bearing mice after the initiation of drug injections.Results: The simultaneous-dosing group showed severe leukopenia compared with the saline-treated group. However, the toxicity was reduced in the intermittent-dosing groups. The DOC-ADR group showed the best survival rate in the dosing groups. In the pharmacokinetic study, ADR and DOC concentrations in plasma, myelocyte cells, and the heart were markedly higher in the simultaneous-dosing group than the intermittent-dosing groups. These results indicate that pharmacokinetic interactions may contribute to the change in leukopenia induced by concurrent administration of ADR and DOC. The antitumor effect in the DOC-ADR group was the highest in the dosing groups.Conclusions: In the present study, the findings suggest that ADR administered 12 h after DOC injection (DOC-ADR group) not only inhibits tumor growth more strongly but also significantly reduces leukopenia compared with results for the simultaneous-dosing (ADR/DOC) group and significantly reduced the number of toxic deaths compared with the other groups.