RELATIONS BETWEEN THE PENETRATION, BINDING AND AVERAGE CONCENTRATION OF CYTOSTATIC DRUGS IN HUMAN TUMOR SPHEROIDS
RELATIONS BETWEEN THE PENETRATION, BINDING AND AVERAGE CONCENTRATION OF CYTOSTATIC DRUGS IN HUMAN TUMOR SPHEROIDS
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DOI：
10.1007/bf00686002
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发表时间：
1992-03-01
影响因子：
3
通讯作者：
CARLSSON, J
中科院分区：
文献类型：
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作者：
ERLANSON, M;DANIELSZOLGAY, E;CARLSSON, J
基于冷冻干燥和蒸汽固定的渗透试验显示了非结合和结合的细胞抑制药物在细胞球体中的空间分布。一些研究表明，药物的外周结合与有限的渗透有关。我们发现颗粒堆积，主要在球体的外围，可能与良好的穿透性平行发生。例如，人胶质瘤球体在与阿霉素孵育15-30分钟后就是这样的情况。经放线菌素D处理后，结肠癌球体表现出较好的穿透性，但也主要在其周围区域表现为颗粒状聚集。Ara-C大量均匀地聚集在结肠癌球体的周边区域，严重延缓了穿透。球体中心区的Ara-C大约需要1h才能达到与培养基中相同的浓度。相反，Ara-C很容易穿透胶质瘤球体，而不会在周围明显聚集。包括洗涤和在无药物培养基中进一步孵育的保留试验表明，广泛积累的区域最常保留药物，表明结合，而其他区域的药物浓度下降。用油离心法从含药培养基中快速分离微球，结果表明微球中柔红霉素的平均浓度早在15min后就超过了培养基中柔红霉素的平均浓度，此时只发生了有限的渗透。我们发现，Ara-C的良好穿透性与胶质瘤球体中的低平均浓度相关，而有限的穿透性与结肠癌球体中的高平均浓度相关。后者的发现归因于药物在球体周围的高度积聚。因此，渗透性和结合力之间以及渗透性和平均药物浓度之间存在着相反的关系。似乎绑定延缓或阻止了穿透，而绑定几乎不会导致更好的穿透。颗粒结合，如观察到的阿霉素和放线菌素D，具有中等良好的渗透性。
A penetration assay based on freeze-drying and vapour fixation was applied to show the spatial distribution of non-bound and bound cytostatic drugs in cellular spheroids. Several studies have proposed that peripheral binding of drugs correlates with limited penetration. We showed that granular accumulation, mainly at the peripheral part of spheroids, might occur in parallel with good penetration. For example, this was the case in human glioma spheroids after incubation with Adriamycin for 15-30 min. Following treatment with actinomycin D, colon carcinoma spheroids exhibited rather good penetration but also showed granular accumulation mainly in their peripheral regions. Ara-C accumulated largely and homogeneously in the peripheral regions of colon carcinoma spheroids and this severely delayed penetration. It took about 1 h for ara-C in the central regions of the spheroids to reach the same concentration as in the culture medium. In contrast, ara-C easily penetrated glioma spheroids without accumulating noticeably at the periphery. Retention tests involving washing and further incubation in drug-free culture medium revealed that the areas demonstrating extensive accumulation most often retained the drug, indicating binding, whereas the concentration of drug in other areas decreased. The oil-centrifugation method, which was used for rapid separation of the spheroids from the drug-containing medium, showed that the average concentration of daunomycin in the spheroids exceeded that in the culture medium as early as after 15 min, by which time only limited penetration had occurred. We found that good penetration of ara-C correlated with a low average concentration in glioma spheroids, whereas limited penetration correlated with a high average concentration in colon carcinoma spheroids. The latter finding was attributable to the high accumulation of drug at the spheroid periphery. Thus, there was an inverse relationship between penetration and binding and between penetration and average drug concentration. It seemed that binding delayed or prevented penetration, whereas little, if any binding resulted in better penetration. Granular binding such as that observed Adriamycin and actinomycin D gave intermediately good penetration.