Huang Y, Waxman S
Department of Medicine, Mount Sinai Medical Center, New York, New York 10029, USA.
Clin Cancer Res. 1998 Oct;4(10):2503-9.
The effect of phenylbutyrate (PB), a nontoxic differentiation inducer, in human colon carcinoma cell lines treated with 5-fluorodeoxyuridine (FUdR) was evaluated. Two HT-29 human colon carcinoma subclones (U4 well differentiated and U9 poorly differentiated) were equally growth inhibited by 16 h of FUdR (0.2 microM) treatment but recovered cell growth in 3-6 days after the removal of FUdR. PB as a single agent had minimal effect on cell growth, but after FUdR treatment, PB inhibited cell growth for 12 days. The inhibition of cell growth in FUdR-treated cells by PB was more sustained in U4 than U9 cells and was associated with an increased and sustained expression of p21waf1 protein, secretion of transforming growth factor beta1, mediators of p53-dependent or -independent G1 cell cycle arrest, and an increase in the alkaline phosphatase activity as well, considered a marker of differentiation in colon carcinoma cells. These effects of PB were seen only in FUdR-pretreated cells because PB alone had minimal effect on the expression of these genes. The sequential use of FUdR followed by PB in patients with colon carcinoma should be explored because two subclones of HT29, irrespective of their state of differentiation, respond to this clinically achievable regimen.
评估了无毒分化诱导剂苯丁酸盐（PB）对用5-氟脱氧尿苷（FUdR）处理的人结肠癌细胞系的影响。两个HT-29人结肠癌亚克隆（U4分化良好，U9分化不良）在接受16小时的FUdR（0.2微摩尔）处理后均受到同等程度的生长抑制，但在去除FUdR后3至6天恢复细胞生长。PB作为单一药物对细胞生长的影响最小，但在FUdR处理后，PB抑制细胞生长达12天。PB对经FUdR处理的细胞的生长抑制在U4细胞中比在U9细胞中更持久，并且与p21waf1蛋白的表达增加和持续、转化生长因子β1的分泌、p53依赖性或非依赖性G1细胞周期停滞的介质以及碱性磷酸酶活性的增加有关，碱性磷酸酶活性增加也被认为是结肠癌细胞分化的标志物。PB的这些作用仅在经FUdR预处理的细胞中可见，因为单独的PB对这些基因的表达影响最小。对于结肠癌患者，应探索先使用FUdR再使用PB的序贯治疗方法，因为HT29的两个亚克隆，无论其分化状态如何，都对这种临床上可行的治疗方案有反应。
