Aharon M, Ben Valid I, Dvilansky A, Nathan I
Department of Hematology, Soroka University Hospital of Kupat Holim, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Anticancer Res. 1995 Sep-Oct;15(5B):2071-6.
The effect of various tyrosine protein kinase inhibitors on processes involved in the antiproliferative effect of interferon-gamma on WISH cells was studied. Following 24 hr treatment interferon-gamma inhibited thymidine incorporation into DNA and thymidine kinase activity, but no significant effect on cell number was observed. The isoflavonoid, genistein, which is a specific inhibitor of tyrosine protein kinase, reversed the inhibition in thymidine incorporation caused by the cytokine in a dose dependent manner. Prunetin, a member of the same group, did not significantly antagonize this effect. N alpha-tosyl-L-lysyl-chloromethane, a serine protease inhibitor which also serves as a tyrosine protein kinase inhibitor, partially reversed the effect of interferon-gamma at a concentration of 100 microM. The bioflavonoid, quercetin, a non-specific tyrosine protein kinase inhibitor, at a concentration of 30 microM completely abolished the action of interferon-gamma on thymidine incorporation. Genistein completely reversed the inhibition of thymidine kinase exerted by interferon, while quercetin had only a slight effect. However, the drugs could not antagonize the antiproliferative effect of interferon following 48 hr incubation, as measured by reduction of cell number. The results indicate that tyrosine protein kinase may play a role in the effects of interferon on thymidine metabolism and thymidine kinase activity. The differential effects of the inhibitors on thymidine metabolism and cell proliferation could support dissociation between the effect of interferon-gamma on these processes. Alternatively, this dissociation of effects could point to the limited use of inhibitors in clarifying modes of action as described.
研究了各种酪氨酸蛋白激酶抑制剂对干扰素-γ对WISH细胞抗增殖作用相关过程的影响。经过24小时处理后，干扰素-γ抑制了胸苷掺入DNA以及胸苷激酶活性，但未观察到对细胞数量有显著影响。异黄酮染料木黄酮是酪氨酸蛋白激酶的特异性抑制剂，它以剂量依赖的方式逆转了细胞因子引起的胸苷掺入抑制作用。同一类别的鼠李素对这种作用没有明显的拮抗作用。Nα-对甲苯磺酰-L-赖氨酰氯甲烷是一种丝氨酸蛋白酶抑制剂，也可作为酪氨酸蛋白激酶抑制剂，在浓度为100微摩尔时部分逆转了干扰素-γ的作用。生物类黄酮槲皮素是一种非特异性酪氨酸蛋白激酶抑制剂，在浓度为30微摩尔时完全消除了干扰素-γ对胸苷掺入的作用。染料木黄酮完全逆转了干扰素对胸苷激酶的抑制作用，而槲皮素只有轻微作用。然而，通过细胞数量减少来衡量，在孵育48小时后，这些药物无法拮抗干扰素的抗增殖作用。结果表明，酪氨酸蛋白激酶可能在干扰素对胸苷代谢和胸苷激酶活性的作用中发挥作用。抑制剂对胸苷代谢和细胞增殖的不同作用可能支持干扰素-γ对这些过程的作用之间存在解离。或者，这种作用的解离可能表明所描述的抑制剂在阐明作用模式方面的用途有限。
