SLOW PENETRATION OF ANTHRACYCLINES INTO SPHEROIDS AND TUMORS - A THERAPEUTIC ADVANTAGE
SLOW PENETRATION OF ANTHRACYCLINES INTO SPHEROIDS AND TUMORS - A THERAPEUTIC ADVANTAGE
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DOI：
10.1007/bf02897199
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发表时间：
1990-01-01
影响因子：
3
通讯作者：
DURAND, RE
中科院分区：
文献类型：
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作者：
DURAND, RE
尽管有明确证据表明蒽环类抗生素对实验性肿瘤或多细胞球体的有效渗透较差，但这些药物对多种实体瘤表现出临床活性。为了理解这一明显的矛盾，我们使用中国仓鼠V79球体系统和流式细胞术技术对阿霉素和柔红霉素进行球体内药理学研究。我们的结果表明，蒽环类药物向球体内层细胞的缓慢递送是由于外层细胞对药物的快速结合。暴露后，当细胞保持在完整球体内时，蒽环类药物的保留比球体分散时更有效，从而导致原位细胞毒性显著增强。这一结果表明，在试图通过使用常规细胞培养系统、暴露后立即分散的球体或实验动物肿瘤切除试验来预测药物的抗肿瘤功效时，需要相当谨慎。此外，我们的结果表明，需要对多药耐药（MDR）表型对于被其他含药细胞包围的细胞（相对于无药培养基中的单个细胞）的意义进行批判性评估。
Despite clear evidence that the effective penetration of the anthracycline antibiotics into experimental tumors or multicell spheroids is poor, these drugs exhibit clinical activity against a variety of solid tumors. In an attempt to understand this apparent contradiction, we used the Chinese hamster V79 spheroid system and flow cytometry techniques for intra-spheroid pharmacological studies of doxorubicin and daunomycin. Our results indicate that the slow delivery of the anthracyclines to the inner cells of spheroids is due to the rapid binding of the drug by cells in the outer layers. After exposure, the anthracyclines are retained much more effectively when cells remain in intact spheroids than when the spheroids have been dispersed, resulting in considerably more cytotoxicity in situ. This result indicates a need for considerable caution in attempting to predict the anti-tumor efficacy of drugs by using either conventional cell-culture systems, spheroids that have been disaggregated immediately post-exposure, or excision assays of tumors from experimental animals. Furthermore, our results suggest the need for a critical evaluation of the significance of the multidrug resistance (MDR) phenotype for cells surrounded by other drug-containing cells as opposed to single cells in drug-free culture medium.