Natale R B, Cody R L, Simon M S, Wheeler R H
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0504.
Cancer Chemother Pharmacol. 1993;31(6):485-8. doi: 10.1007/BF00685040.
Aclarubicin is an anthracycline antibiotic that differs from doxorubicin in its structure, mechanism of action, and preclinical toxicity profile, especially its reduced cardiotoxicity. We therefore conducted a side-by-side in vivo and in vitro trial of this agent in metastatic breast-cancer patients and their biopsied tumor specimens, respectively. Aclarubicin (100 mg/m2) was given by intravenous infusion every 3 weeks to 22 patients with objectively measurable metastatic breast cancer, 15 of whom had not previously received doxorubicin. The dose-limiting toxicity consisted primarily of leukopenia and severe nausea and vomiting. No objective response was observed in the 19 evaluable patients. After disease progression, 10 of the 15 doxorubicin-naive patients were treated with doxorubicin; 6 patients achieved a partial response, including 4 who responded to doxorubicin alone and 2 who responded to doxorubicin in combination with thiotepa and vinblastine. Tumor specimens were obtained from 14 of the 22 patients prior to the start of therapy and were tested for in vitro sensitivity to aclarubicin and doxorubicin using a soft agar colony-forming assay. Adequate colony growth occurred in 9 of 14 cultured tumor specimens. All 9 specimens, including 3 obtained from doxorubicin-naive patients, demonstrated in vitro resistance to aclarubicin. In all, 1 of 3 specimens taken from doxorubicin-naive patients demonstrated in vitro sensitivity to doxorubicin, whereas 6 tumor specimens obtained from patients who had undergone prior doxorubicin therapy demonstrated in vitro resistance. The patient whose tumor demonstrated in vitro doxorubicin sensitivity responded to a doxorubicin regimen after failing aclarubicin treatment; in vitro doxorubicin resistance correlated with clinical resistance in all cases. We conclude that aclarubicin is inactive in metastatic breast cancer at the dose and schedule used. Side-by-side in vivo and in vitro trials are feasible and could be useful in the development of investigational agents with activity greater than that of aclarubicin and, particularly, in the evaluation of analogs of clinically active drugs.
阿柔比星是一种蒽环类抗生素，其结构、作用机制和临床前毒性特征与多柔比星不同，尤其是心脏毒性较低。因此，我们分别对转移性乳腺癌患者及其活检肿瘤标本进行了该药物的体内和体外平行试验。每3周给22例有客观可测量转移性乳腺癌的患者静脉输注阿柔比星（100mg/m²），其中15例患者此前未接受过多柔比星治疗。剂量限制性毒性主要包括白细胞减少和严重的恶心、呕吐。19例可评估患者中未观察到客观缓解。疾病进展后，15例未接受过多柔比星治疗的患者中有10例接受了多柔比星治疗；6例患者获得部分缓解，其中4例仅对多柔比星有反应，2例对多柔比星联合噻替哌和长春碱有反应。在治疗开始前从22例患者中的14例获取肿瘤标本，使用软琼脂集落形成试验检测其对阿柔比星和多柔比星的体外敏感性。14个培养的肿瘤标本中有9个出现了足够的集落生长。所有9个标本，包括3个从未接受过多柔比星治疗患者获取的标本，均显示对阿柔比星有体外耐药性。总共，从未接受过多柔比星治疗患者获取的3个标本中有1个显示对多柔比星有体外敏感性，而从接受过多柔比星治疗患者获取的6个肿瘤标本显示有体外耐药性。其肿瘤显示对多柔比星有体外敏感性的患者在阿柔比星治疗失败后对多柔比星方案有反应；在所有病例中，体外多柔比星耐药性与临床耐药性相关。我们得出结论，按所用剂量和方案，阿柔比星在转移性乳腺癌中无活性。体内和体外平行试验是可行的，对于开发活性高于阿柔比星的研究药物，特别是在评估临床活性药物类似物方面可能有用。
