Zee-Cheng R K, Cheng C C
Department of Pharmacology, University of Kansas Cancer Center, Kansas City.
Methods Find Exp Clin Pharmacol. 1989 Jul-Aug;11(7-8):439-529.
Chemotherapy is a major therapeutic approach for the treatment of both localized and metastasized cancers. Since anticancer drugs are neither specific nor targeted to the cancer cells, improved delivery of anticancer drugs to tumor tissues in humans appears to be a reasonable and achievable challenge. Scientists are working to increase the availability of drug for tumor uptake by 1) delaying the release preparations for long-lasting actions; 2) using liposome-entrapped drugs for prolonged effect or reduced toxicity; 3) administrating inert, non-toxic prodrugs for specific activation at the tumor site; 4) delivering the antibody-mediated drugs; or 5) conjugating site-specific carriers to direct the drug to the tumor target. The latter depends heavily on pharmacokinetic investigations. Some success has been achieved in enhancing the efficacy and reducing the toxicity of drugs. Pharmacokinetic and pharmacodynamic considerations are two areas which have been focused toward the quantitative pharmacological studies of anticancer drugs in this manuscript. This review covers biodistribution and elimination, furnishing information on body clearance and unveiling sites of major metabolism; administration of anticancer drugs via various routes for optimal utilization; intra-arterial infusion for localized tumors, intrathecal, intraperitoneal and intrapleural injection for regional cavity administration. Conventional delivery routes, doses, pharmacokinetics data and elimination routes of therapeutic anticancer drugs are tabled. General approaches for delivery of anticancer drugs in achieving therapeutic improvements are outlined and correlated. Mechanism of drug resistance, and specific changes affecting the delivery of available chemotherapeutic agents, as well as the drugs to restore the sensitivities to agents of resistant tumor cells, are discussed. This monograph covers the developments and progress in the delivery of anticancer drugs in two approaches: the theoretical approach, including pharmacokinetic and pharmacodynamic considerations, therapeutic implications and mechanism of drug resistance, and the practical approach, including the physical, chemical, biochemical and physiological considerations. Among these, the physical approach for the delivery of anticancer agents to target sites (via microparticulate drug carriers: nanoparticles, liposomes, microspheres and activated carbon as well as the magnetic microcapsules) has shown recognizable improvements in prolonging anticancer effects and reducing toxicities. Implantable pumps and reservoirs for regional chemotherapy provide external control of delivery rate. The implanted systems, in general, yield better results than the traditional treatments in the treatment of liver and brain cancer. Chemical approaches for the improvement of drug delivery use prodrugs, biodegradable polymers and macromolecular matrix techniques.(ABSTRACT TRUNCATED AT 400 WORDS)
化疗是治疗局部和转移性癌症的主要治疗方法。由于抗癌药物既不具有特异性，也不靶向癌细胞，因此改善抗癌药物在人体肿瘤组织中的递送似乎是一项合理且可实现的挑战。科学家们正在努力通过以下方式提高肿瘤摄取药物的可用性：1）延迟释放制剂以实现长效作用；2）使用脂质体包裹的药物以延长作用时间或降低毒性；3）施用惰性、无毒的前药以在肿瘤部位进行特异性活化；4）递送抗体介导的药物；或5）将位点特异性载体偶联以将药物导向肿瘤靶点。后者在很大程度上依赖于药代动力学研究。在提高药物疗效和降低毒性方面已经取得了一些成功。药代动力学和药效学考量是本手稿中针对抗癌药物定量药理学研究的两个重点领域。本综述涵盖了生物分布和消除，提供了关于机体清除率的信息并揭示了主要代谢部位；通过各种途径给药以实现最佳利用；局部肿瘤的动脉内输注、鞘内、腹腔内和胸腔内注射用于区域腔室给药。列出了治疗性抗癌药物的传统给药途径、剂量、药代动力学数据和消除途径。概述并关联了实现治疗改善的抗癌药物递送的一般方法。讨论了耐药机制以及影响现有化疗药物递送的具体变化，以及使耐药肿瘤细胞恢复对药物敏感性的药物。这本专著涵盖了抗癌药物递送在两种方法上的发展和进展：理论方法，包括药代动力学和药效学考量、治疗意义和耐药机制；以及实践方法，包括物理、化学、生物化学和生理学考量。其中，将抗癌剂递送至靶位点的物理方法（通过微粒药物载体：纳米颗粒、脂质体、微球和活性炭以及磁性微胶囊）在延长抗癌作用和降低毒性方面已显示出显著改善。用于区域化疗的可植入泵和储器可提供给药速率的外部控制。一般来说，植入系统在治疗肝癌和脑癌方面比传统治疗产生更好的效果。改善药物递送的化学方法使用前药、可生物降解聚合物和大分子基质技术。（摘要截断于400字）
