Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors
Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors
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DOI：
10.1158/1078-0432.ccr-06-0226
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发表时间：
2006-07-01
影响因子：
11.5
通讯作者：
Dewhirst, Mark W.
中科院分区：
文献类型：
--
作者：
Hauck, Marlene L.;LaRue, Susan M.;Dewhirst, Mark W.
目的：研究低温敏感脂质体（LTSL）包裹的阿霉素对犬实体瘤的最大耐受剂量、剂量限制性毒性和药代动力学特征。实验设计：对患有实体瘤（癌或肉瘤）的私人养狗进行治疗。肿瘤不累及骨，位于可局部热疗的部位。在标准的I期剂量递增研究中，在局部肿瘤热疗期间给予ltsl -阿霉素（0.7-1.0 mg/kg静脉注射）超过30分钟。计划进行三次治疗，间隔3周。另外一个月的毒性监测。在第一个治疗周期评估药代动力学。结果：21例患者入组，其中肉瘤18例，癌3例。4级中性粒细胞减少和继发于肝功能衰竭的急性死亡，可能与药物有关，是剂量限制性毒性。最大耐受剂量为0.93 mg/kg。除肾脏损害外，其他毒性与阿霉素游离给药后观察到的结果一致。在接受>= 2剂量ltsl -阿霉素治疗的20只狗中，12只病情稳定，6只对治疗有部分反应。与市售的阿霉素相比，游离阿霉素的药代动力学变量更接近。在1.0 mg/kg剂量下，肿瘤药物浓度平均为9.12±6.17 ng/mg组织。结论：ltsl -阿霉素为改善实体肿瘤的药物递送提供了一种新的途径。该药物耐受性良好，在这些患者中产生了良好的反应。有必要在人类患者中进行进一步的评估。
Purpose: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors.Experimental Design: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle.Results: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received >= 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue.Conclusion: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.