苯丁酸氮芥在慢性淋巴细胞白血病的作用机制。
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Begleiter, Mowat M,以色列LG,约翰斯顿简森-巴顿
苯丁酸氮芥在慢性淋巴细胞白血病的作用机制。
Leuk淋巴瘤。1996年10月,23 (3 - 4):187 - 201。
- PubMed ID
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9031099 (在PubMed]
- 文摘
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慢性淋巴细胞白血病(CLL)是最常见的白血病在西方国家,但临床表现和疾病进展的速度是高度可变的。当需要治疗时最常用的疗法是氮芥烷化剂,苯丁酸氮芥(CLB),有或没有强的松。虽然CLB已经用于治疗慢性淋巴细胞白血病的四十年这个代理在慢性淋巴细胞白血病的确切的作用机制尚不清楚。在肿瘤增殖模型系统的研究已经证明CLB可以绑定到各种细胞结构,如膜,RNA,蛋白质和DNA;然而,DNA交联似乎是最重要的是这些系统的抗肿瘤活性。此外,许多不同的机制有助于CLB阻力在这些肿瘤模型包括药物代谢增加,DNA修复和CLB解毒所产生的高浓度的谷胱甘肽(GSH),谷胱甘肽S-transferase(销售税)活动。但是,与体外肿瘤模型,慢性淋巴细胞白血病细胞一般不扩散和研究在慢性淋巴细胞白血病细胞DNA交联的假设提出了质疑的抗肿瘤作用的主要机制是CLB在这个疾病。CLB慢性淋巴细胞白血病细胞发生凋亡,这似乎与这个代理的临床疗效。因此,烷基化的细胞目标DNA以外,还可以诱导细胞凋亡,可能导致CLB的活动。如p53的基因改变,mdm-2 bcl - 2、bax控制进入细胞凋亡可能导致耐药性。 Loss of wild-type p53 by mutation or deletion occurs in 10 to 15% of CLL patients and appears to correlate strongly with poor clinical response to CLB. The induction of apoptosis by CLB is paralleled by an increase in P53 and Mdm-2 but this increase in not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pathways. The level of Mdm-2 mRNA in the CLL cells is not a useful predictor of drug sensitivity. In addition, although Bax and Bcl-2 are important regulators of apoptosis and the levels of these proteins are elevated in CLL cells compared with normal B cells, the levels of Bax and Bcl-2, or the Bax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside analogs may produce cell death in CLL by a P53 dependent pathway other agents, such as dexamethasone or vincristine, may act through P53-independent pathways.