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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >The use of liposomal anticancer agents to determine the roles of drug pharmacodistribution and P-glycoprotein (PGP) blockade in overcoming multidrug resistance (MDR).
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The use of liposomal anticancer agents to determine the roles of drug pharmacodistribution and P-glycoprotein (PGP) blockade in overcoming multidrug resistance (MDR).

机译：使用脂质体抗癌剂确定药物的药物分布和P-糖蛋白（PGP）阻断在克服多药耐药性（MDR）中的作用。

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Many attempts to circumvent P-glycoprotein (PGP)-based multidrug resistance (MDR) in cancer chemotherapy have utilized PGP blocking agents (also referred to as MDR modulators), which are co-administered with the anticancer drug. This approach is based on the premise that inhibiting PGP function will result in increased accumulation of many anticancer drugs in the tumor cells and restore full antitumor activity. However, co-administration of MDR modulators with anticancer drugs has often resulted in exacerbated toxicity of the anticancer drugs and limited chemosensitization of MDR tumors. These problems appear to be related to MDR modulator blockade of PGP excretory functions in healthy tissues, such as liver and kidney, which markedly reduces anticancer drug clearance properties. Two consequences of these pharmacokinetic interactions are: 1. Increased toxicity due to modulator-induced changes in biodistribution properties of the anticancer drug. 2. Problems interpreting preclinical and clinical data with respect to: a) Are therapeutic improvements due to altered pharmacokinetics or PGP modulation within the tumor cells? And, b) Does decreasing the anticancer drug dose to that which is equitoxic in the absence of the modulator potentially compromise tumor therapy due to decreased anticancer drug levels in the tumor tissue? Although many of the difficulties associated with co-administration of MDR modulators and anticancer drugs are manifested by toxicity effects, it is ultimately the ability to obtain effective antitumor activity against resistant tumors that will determine the utility of chemosensitization approaches. Liposomes appear to be well suited to solve many of the problems noted above that are associated with conventional anticancer drugs and MDR modulators. In view of these considerations, we have hypothesized that inadequate tumor delivery of anticancer agents and selectivity of PGP modulation are primarily responsible for the attenuated therapy of extravascular MDR solid tumors overexpressing PGP. Liposomal carriers have been utilized to provide tumor selective delivery of anticancer agents as well as to circumvent many toxicities associated with these agents by altering the pharmacodistribution properties of encapsulated drugs (1-4). Given the pharmacokinetic changes induced by the MDR modulators on non-encapsulated doxorubicin (DOX), we proposed that liposomes may limit these effects by virtue of their ability to reduce the exposure of encapsulated DOX to the kidneys and alter clearance of DOX in the liver (5,6). These tissues appear to be key factors involved in modulator-induced DOX pharmacokinetic changes (7). In conjunction with these toxicity buffering effects, the effect of PGP blockade on the cellular uptake of DOX in the tumor may be able to be selectively increased using liposomal carriers. This is based on the ability of small liposomes to passively extravasate in tumors (1,2,8,9) as well as their inability to accumulate in healthy susceptible tissues. By studying the toxicity and efficacy properties of liposome encapsulated DOX in combination with the MDR modulator PSC 833 we have been able to demonstrate that two factors play a major role in determining the effectiveness of chemosensitization approaches to overcome MDR; 1) optimizing selective localization of anticancer drug localization in tumor tissue and 2) effective blockade of PGP in tumor cells under conditions that do not compromise anticancer drug accumulation into the tumor. Failure to achieve both of these conditions simultaneously may be expected to result in substantially reduced therapy of MDR tumors.
机译：在癌症化学疗法中许多规避基于P糖蛋白（PGP）的多药耐药性（MDR）的尝试都使用了与抗癌药共同使用的PGP阻断剂（也称为MDR调节剂）。该方法基于以下前提：抑制PGP功能将导致多种抗癌药物在肿瘤细胞中的积累增加，并恢复完全的抗肿瘤活性。然而，MDR调节剂与抗癌药的共同给药常常导致抗癌药的毒性加剧和MDR肿瘤的化学敏感性有限。这些问题似乎与MDR调节剂阻断健康组织（例如肝脏和肾脏）中PGP的排泄功能有关，这显着降低了抗癌药物的清除特性。这些药代动力学相互作用的两个结果是：1.由于调节剂诱导的抗癌药物生物分布特性的变化，毒性增加。 2.关于以下方面的临床前和临床数据的解释问题：a）治疗改进是否归因于肿瘤细胞内药代动力学或PGP调节的改变？并且，b）由于肿瘤组织中抗癌药物水平的降低，将抗癌药物的剂量降低至不存在调节剂时的等毒性剂量是否可能损害肿瘤治疗？尽管与MDR调节剂和抗癌药物共同给药相关的许多困难通过毒性作用得以体现，但最终获得针对耐药性肿瘤的有效抗肿瘤活性的能力将决定化学增敏方法的实用性。脂质体似乎非常适合解决与常规抗癌药和MDR调节剂相关的上述许多问题。鉴于这些考虑，我们假设抗癌药的肿瘤递送不足和PGP调节的选择性是造成过表达PGP的血管外MDR实体瘤减毒治疗的主要原因。脂质体载体已被用于提供抗癌剂的肿瘤选择性递送，以及通过改变被包封的药物的药理分布特性来规避与这些剂相关的许多毒性（1-4）。鉴于MDR调节剂对未包囊的阿霉素（DOX）诱导的药代动力学变化，我们提出脂质体可通过减少包囊的DOX对肾脏的暴露并改变肝脏中DOX的清除能力来限制这些作用（ 5,6）。这些组织似乎是调节剂诱导的DOX药代动力学变化的关键因素（7）。结合这些毒性缓冲作用，可以使用脂质体载体选择性地增加PGP阻断对肿瘤中DOX细胞摄取的影响。这是基于小脂质体在肿瘤中被动渗出的能力（1,2,8,9）以及它们无法在健康易感组织中积累的能力。通过研究脂质体包裹的DOX与MDR调节剂PSC 833的毒性和功效特性，我们已经证明了两个因素在决定化学增敏方法克服MDR的有效性方面起着主要作用。 1）优化抗癌药在肿瘤组织中的选择性定位，以及2）在不损害抗癌药向肿瘤内蓄积的条件下有效阻断肿瘤细胞中的PGP。无法同时达到这两个条件可能会导致MDR肿瘤的治疗大大减少。

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