在慢性淋巴细胞白血病治疗中，磷酸肌醇3激酶δ抑制剂的代谢和毒理学考虑。
Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia.
发表日期：2023 Sep 15
作者：
Magdalena Witkowska, Agata Majchrzak, Paweł Robak, Anna Wolska-Washer, Tadeusz Robak
来源：
Experimental Hematology & Oncology
摘要：
磷脂酰肌醇3-激酶δ（PI3Kδ）抑制剂是一类主要用于治疗B细胞恶性肿瘤的新型药物。它们通过抑制PI3K/AKT/mTOR通路中的一个或多个酶来发挥作用。伊德利莫司是一种首个上市的PI3Kδ抑制剂，对B细胞淋巴恶性肿瘤患者有效。本文回顾了PI3Kδ抑制剂的化学结构、作用机制以及代谢和毒理特性，并讨论了它们在单药治疗和与其他药物联合治疗慢性淋巴细胞白血病（CLL）中的临床应用。我们在PubMed、Web of Science和Google Scholar上对英文文章进行了检索。PI3Kδ抑制剂对治疗包括CLL在内的B细胞恶性肿瘤具有潜力。然而，它们的使用也与严重的毒性反应相关，包括肺炎、细胞减少症、肝炎和皮疹。正在开发的新药通过新型方案和/或联合用药来减少毒性。开发新型PI3Kδ抑制剂可能有助于减轻毒性，提高CLL和其他B细胞淋巴恶性肿瘤患者的疗效。
Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies.This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL). A search was conducted of PubMed, Web of Science, and Google Scholar for articles in English.PI3Kδ inhibitors hold potential for the treatment of B-cell malignancies including CLL. However, their use is also associated with severe toxicities, including pneumonia, cytopenias, hepatitis, and rash. Newer drugs are in development to reduce toxicity with novel schedules and/or combinations.The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.