Mastronardi L, Farah J O, Puzzilli F, Ruggeri A
Civilian Hospital of Terni, Department of Neurological Sciences Neurosurgery, Italy.
Clin Neurol Neurosurg. 1998 Jun;100(2):89-93. doi: 10.1016/s0303-8467(98)00004-3.
Glioma cells express high protein kinase C (PKC) activity, which may represent an important therapeutic target. Tamoxifen (TAM) has moderate PKC-inhibiting activity, blocking DNA synthesis and cellular proliferation in human glioma cells at concentrations that can be achieved therapeutically. Carboplatin (CBDCA), a second-generation platinum derivative, induces intra- and interstrand DNA-protein crosslinks producing inhibition of tumor-cell growth. In the present study, the effect of TAM, CBDCA, and the combination of both was evaluated against the human established U-138 glioma cell line during the exponential growth phase (48-72 h) by means of both the Biorad protein assay (BPA) method and Trypan blue exclusion study (TBES). Both TAM and CBDCA reduced the cellular growth rate, with a median 50%-inhibiting concentration (IC50) of 12.5 microM for TAM and 350 microM for CBDCA. The U-138 glioma cell line showed a moderate response to 100 microM of CBDCA, with < or = 10% reduction of the growth rate. The association of both chemotherapeutic agents induced a 98% reduction of the IC50 dose of TAM (0.1 microM), and a 71% reduction of the IC50 dose of CBDCA (100 microM). During the combinational TAM CBDCA exposure we observed a cytotoxic effect of TAM at concentrations lower than 0.1 microM, not recognized using it as a single drug. The differences observed among the IC50 doses (TAM, CBDCA, TAM-CBDCA) and among treated and untreated matched control cells were statistically significant (P < 0.01). Our results confirm previous observations about the efficacy in vitro of TAM against human glioma cell lines and show a marked enhancement of this activity by CBDCA.
胶质瘤细胞表达高蛋白激酶C（PKC）活性，这可能是一个重要的治疗靶点。他莫昔芬（TAM）具有中等程度的PKC抑制活性，在可通过治疗达到的浓度下，能阻断人胶质瘤细胞中的DNA合成和细胞增殖。第二代铂衍生物卡铂（CBDCA）可诱导链内和链间DNA - 蛋白质交联，从而抑制肿瘤细胞生长。在本研究中，通过伯乐蛋白质测定法（BPA）和台盼蓝排斥试验（TBES），评估了TAM、CBDCA以及两者联合使用对处于指数生长期（48 - 72小时）的人源U - 138胶质瘤细胞系的作用。TAM和CBDCA均降低了细胞生长速率，TAM的半数抑制浓度（IC50）中位数为12.5微摩尔，CBDCA为350微摩尔。U - 138胶质瘤细胞系对100微摩尔的CBDCA表现出中等反应，生长速率降低≤10%。两种化疗药物联合使用使TAM的IC50剂量降低了98%（至0.1微摩尔），CBDCA的IC50剂量降低了71%（至100微摩尔）。在TAM与CBDCA联合处理期间，我们观察到TAM在浓度低于0.1微摩尔时具有细胞毒性作用，而单独使用时未观察到这种作用。在IC50剂量（TAM、CBDCA、TAM - CBDCA）之间以及处理组与未处理的匹配对照细胞之间观察到的差异具有统计学意义（P < 0.01）。我们的结果证实了先前关于TAM对人胶质瘤细胞系体外疗效的观察，并表明CBDCA可显著增强这种活性。
