Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
Curr Med Chem. 2009;16(35):4632-43. doi: 10.2174/092986709789878229.
Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half live, change the biodistribution and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Duplex and multiplex drugs consist of distinct active drugs with different mechanisms of action, which are linked to each other with either a lipid or a phosphodiester. Enzymatic cleavage of such a prodrug inside the cell releases the drug or the phosphorylated form of the drug. Antitumor activity of cytotoxic drugs can also be enhanced by the use of nanoparticles as carriers. Nanoparticles have the advantage of high stability, high carrier capacity, incorporation of hydrophobic and hydrophilic compounds and variable routes of administration. Encapsulating drugs in liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. Nanoparticles and liposomes can be used to target drugs either actively or passively to the tumor. In this review we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy)nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems. We expect that combining different strategies could further increase the efficacy of these compounds.
目前用于癌症治疗的许多药物都存在局限性，例如诱导耐药性和/或较差的生物半衰期，这降低了它们的临床疗效。为了克服这些局限性，已经探索了几种策略。通过将亲脂性部分连接到（脱氧）核苷类似物上来进行化学修饰，应该能够提高血浆半衰期，改变生物分布并提高药物的细胞摄取率。将亲脂性部分连接到磷酸化（脱氧）核苷类似物上，将绕过（脱氧）核苷类似物的限速激活步骤，从而提高药物的活性。双链和多链药物由具有不同作用机制的不同活性药物组成，它们通过脂质或磷酸二酯键彼此连接。在细胞内，这种前药的酶促裂解会释放药物或药物的磷酸化形式。通过使用纳米粒子作为载体，也可以增强细胞毒性药物的抗肿瘤活性。纳米粒子具有高稳定性、高载药能力、可掺入疏水性和亲水性化合物以及可变给药途径的优势。将药物包封在脂质体中可以防止药物在血浆中酶解，并使亲脂性化合物能够到达肿瘤部位。纳米粒子和脂质体可以主动或被动地将药物靶向肿瘤。在这篇综述中，我们讨论了通过化学修饰和替代递药系统来提高经典（脱氧）核苷和氟嘧啶化合物疗效方面所取得的相当大的进展。我们预计，结合不同的策略可以进一步提高这些化合物的疗效。
