PHARMACOKINETIC CYTOKINETIC PRINCIPLES IN THE CHEMOTHERAPY OF SOLID TUMORS
PHARMACOKINETIC CYTOKINETIC PRINCIPLES IN THE CHEMOTHERAPY OF SOLID TUMORS
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DOI：
10.1111/j.1440-1681.1995.tb01943.x
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发表时间：
1995-11-01
影响因子：
2.9
通讯作者：
FINLAY, GJ
中科院分区：
文献类型：
--
作者：
BAGULEY, BC;FINLAY, GJ
1.实体瘤具有各种特性，这些特性往往会使细胞毒性剂的作用最小化;特别是肿瘤的低血管密度限制了许多抗肿瘤药物的扩散。这特别适用于已经在化疗中发挥重要作用的两大类抗癌药物：有丝分裂毒药和拓扑异构酶毒药。这些化合物与蛋白质和/或DNA强烈结合，并且它们从血流扩散到实体瘤中是缓慢的，它们从肿瘤组织中的清除也是缓慢的。这里提出的具体问题是，这些类型的抗癌化合物在以低浓度长时间给药（模拟实体瘤中的条件）时是否比在相应的高浓度短时间给药（模拟宿主组织中的条件）时更具细胞毒性。可能涉及两种可能的原理，第一种基于细胞动力学考虑，第二种基于药物细胞毒性的自抑制。使用培养的人类癌细胞，我们已经表明，作用于有丝分裂细胞的紫杉醇和作用于S期细胞的喜树碱是第一原理的例子。短时间暴露于高药物浓度比暴露于相应较低药物浓度较长时间的细胞毒性小得多（相同浓度×暴露时间），我们还表明，药物DACA（N-[2-（二甲氨基）乙基]吖啶-4-甲酰胺），在本实验室开发的，目前正在进行临床试验，通过细胞毒性的自我抑制的原理，达到相同的结果.将药物作用的细胞动力学或自抑制特征与药物在肿瘤中的药代动力学相匹配，可以提供具有增强的抗肿瘤作用的新药。
1. The solid tumour has various properties which tend to minimize the effects of a cytotoxic agent; the low vascular density of tumours, in particular, limits the diffusion of many anti-tumour drugs.2. This applies particularly to two general classes of anticancer drugs which already play an important role in chemotherapy: mitotic poisons and topoisomerase poisons. Such compounds bind strongly to proteins and/or DNA, and their diffusion from the bloodstream into solid tumours is slow, as is their clearance from tumour tissue.3. The specific question posed here is whether anti-cancer compounds of these types are more cytotoxic when administered at a low concentration for a long time (mimicking conditions in solid tumours) than at a correspondingly high concentration for a short time (mimicking conditions in host tissue), Two possible principles may be involved, the first based on cytokinetic considerations and the second on self-inhibition of drug cytotoxicity.4. Using cultured human cancer cells we have shown that taxol, which acts on mitotic cells and camptothecin, which acts on S-phase cells, are examples of the first principle. Exposures to high drug concentrations for short times are much less cytotoxic than exposure to correspondingly lower drug concentrations for a longer time (with the same concentration X time of exposure), We also show that the drug DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), developed in this laboratory and currently undergoing clinical trial, achieves the same result through the principle of self-inhibition of cytotoxicity.5. Matching of the cytokinetic or self-inhibitory profile of a drug's action with the pharmacokinetics of drug in tumours may provide new drugs with increased anti-tumour effects.