噻唑呋林和二氟脱氧胞苷对分化和细胞毒性的协同作用。

Synergistic action of tiazofurin and difluorodeoxycytidine on differentiation and cytotoxicity.

作者信息

Ban J, Weber G

机构信息

Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.

出版信息

Biochem Biophys Res Commun. 1992 Apr 30;184(2):551-9. doi: 10.1016/0006-291x(92)90625-u.

DOI:10.1016/0006-291x(92)90625-u

PMID:1349474

Abstract

Tiazofurin (TR), an inhibitor of IMP dehydrogenase, causes remissions and induced differentiation in human leukemia through lowering the concentrations of GTP and dGTP. A deoxycytidine analog, difluorodeoxycytidine (DFDC), is an anti-tumor agent phosphorylated by deoxycytidine kinase, resulting in decreased concentration of dCTP, leading to inhibition of DNA synthesis. In HL-60 cells DFDC induced differentiation and inhibited proliferation in a dose-dependent manner (IC50 = 4 nM); TR provided synergism with DFDC. DFDC inhibited proliferation in OVCAR-5 human ovarian carcinoma cells (IC50 = 25 nM) and colony formation in PANC-1 human pancreatic carcinoma cells (IC50 = 2 nM) and rat hepatoma 3924A cells (IC50 = 22 nM). TR and DFDC are synergistically cytotoxic in hepatoma cells and additive in PANC-1 cells. The two drugs together should be helpful in treating leukemias and solid tumors in humans.

摘要

硫唑嘌呤（TR）是肌苷酸脱氢酶的抑制剂，通过降低GTP和dGTP的浓度，使人类白血病缓解并诱导分化。一种脱氧胞苷类似物，二氟脱氧胞苷（DFDC），是一种由脱氧胞苷激酶磷酸化的抗肿瘤药物，导致dCTP浓度降低，从而抑制DNA合成。在HL-60细胞中，DFDC以剂量依赖性方式诱导分化并抑制增殖（IC50 = 4 nM）；TR与DFDC具有协同作用。DFDC抑制OVCAR-5人卵巢癌细胞的增殖（IC50 = 25 nM）以及PANC-1人胰腺癌细胞（IC50 = 2 nM）和大鼠肝癌3924A细胞（IC50 = 22 nM）的集落形成。TR和DFDC在肝癌细胞中具有协同细胞毒性，在PANC-1细胞中具有相加作用。这两种药物联合应用应有助于治疗人类白血病和实体瘤。