嘌呤核苷类似物的免疫抑制和抗肿瘤的代理人:作用机理和临床活动。
文章的细节
-
引用
复制到剪贴板 -
可观的T, Lech-Maranda E, Korycka,可观的E
嘌呤核苷类似物的免疫抑制和抗肿瘤的代理人:作用机理和临床活动。
咕咕叫地中海化学2006;13 (26):3165 - 89。
- PubMed ID
-
17168705 (在PubMed]
- 文摘
-
嘌呤核苷类似物(机构)的细胞毒性药物的一个重要组织形式活跃在肿瘤和自身免疫性疾病的治疗。他们三个,氟达拉滨(FA)、cladribine (2-chlorodeoxyadenosine 2-CdA)和pentostatin(2脱氧肋间型霉素,DCF)建立了临床活动血液恶性肿瘤和FDA批准。这些药物也在一些自身免疫性diosorders调查。最近四个新颖的机构:clofarabine (CAFdA) nelarabine immucillin H (forodesine bcx - 1777)和8-chloroadenosine (8-Cl-Ado)已经合成并引入临床试验。所有这些药物化学结构类似于腺苷或鸟嘌呤核苷,然而,他们的行动的机制是不同的。FA, 2-CdA CAFdA主要由deoxynucleoside救助需要磷酸化途径。细胞毒性效应产生三磷酸代谢物,纳入DNA,并最终导致程序性细胞死亡。相比之下,DCF不需要在增加等离子体脱氧腺苷磷酸化和结果(墙裙)水平和细胞内的脱氧腺苷三磷酸(dATP)。Nelarabine是arabinosylguanine (ara-G)前体药物,经过转换ara-G是磷酸化ara-G三磷酸(ara-GTP)。ara-GTP积累最终导致细胞凋亡。 Forodesine is a purine nucleoside phosphatase (PNP) inhibitor which blocks intracellular deoxyguanine (dGuo) cleaving to guanine (Guo), but instead converts it to deoxyguanosine triphosphate (dGTP), and similarly to other PNA resulting in apoptosis. 8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action is quite different from other PNA and remains poorly understood. However, it is known that the drug inhibits RNA synthesis, but not DNA. These agents have significant cytotoxic activity against lymphoid and myeloid malignant cells. Moreover, they have deleterious effects on the normal resting lymphocytes. They result in prolonged lymphocyte depletion especially in the CD4 subset of T-cells. Several clinical trials have demonstrated that PNA used alone or in combination with other cytotoxic drugs or monoclonal antibodies shows good efficacy and acceptable toxicity profile in the treatment of lymphoid malignancies. 2-CdA and DCF are drugs of choice in the treatment of hairy cell leukemia. FA and 2-CdA have significant clinical activity in low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. 2-CdA exhibits some activity in progressive multiple sclerosis and other autoimmune disorders. This review will summarize current knowledge concerning the mechanism of action, pharmacological properties, clinical activity and toxicity of PNA accepted for use in clinical practice as well as new agents available for clinical trials.