Robert J
Fondation Bergonié, service de biochimie, Bordeaux, France.
Bull Cancer. 1994 Dec;81 Suppl 2:78s-81s.
Besides the cellular mechanisms of resistance, which can be described in terms of molecular alterations, the lack of sensitivity of a tumour to a drug may result from an inadequacy between the pharmacokinetics of the drug and the kinetics of the tumour cells. Dose and duration of infusion of a drug may govern its activity; the drugs exhibiting a short half-life in plasma and a marked phase-dependence in their mechanism of action have to be administered as continuous infusions. The existence of sanctuary compartments within the body, which are protected by barriers such as the blood-brain barrier, may also contribute to the failure of the molecules unable to cross these barriers. Finally, the tumour cell kinetics may unfavour the general activity of drugs: this is the case of slowly growing tumours, which contain an important proportion of GO cells. The optimisation of the mode of administration of a drug is a requisite for the expression of its activity.
除了可以用分子改变来描述的耐药细胞机制外，肿瘤对药物缺乏敏感性可能是由于药物的药代动力学与肿瘤细胞动力学之间不匹配所致。药物的剂量和输注持续时间可能决定其活性；在血浆中半衰期短且作用机制具有明显时相依赖性的药物必须持续输注给药。体内存在受血脑屏障等屏障保护的“庇护区室”，这也可能导致无法穿过这些屏障的分子失效。最后，肿瘤细胞动力学可能不利于药物的总体活性：生长缓慢的肿瘤就是这种情况，其中含有很大比例的G0期细胞。优化药物给药方式是其活性发挥的必要条件。
