Carducci M A, Nelson J B, Chan-Tack K M, Ayyagari S R, Sweatt W H, Campbell P A, Nelson W G, Simons J W
The Johns Hopkins Oncology Center and The Brady Urological Institute, Baltimore, Maryland 21205, USA.
Clin Cancer Res. 1996 Feb;2(2):379-87.
Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy, has molecular activities distinct from its metabolite, phenylacetate (PA). Both PB and PA promote differentiation in human prostate cancer cell lines, yet little data exist comparing the cytotoxic effects of each drug. We found that PB is more potent than PA in vitro; PB is 1.5-2.5 times more active at inhibiting growth and inducing programmed cell death than PA at clinically achievable doses against each human prostate cancer line studied. PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms. Exposure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis. These PB-induced effects are 2-10 times greater than those of the control or PA. The stereotypical changes of apoptosis can be seen with sodium butyrate at similar concentrations, but not with PA. Prostate cancer cell lines overexpressing P-glycoprotein or possessing heterogeneous molecular alterations, including p53 mutations, are also sensitive to the effects of PB. In vivo, Copenhagen rats treated with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner. These results demonstrate that PB induces cytotoxicity via apoptosis in human prostate cancer, in addition to its differentiating properties.
苯丁酸盐（PB）是一种用于前列腺癌治疗的新型先导化合物，具有与其代谢产物苯乙酸盐（PA）不同的分子活性。PB和PA均可促进人前列腺癌细胞系的分化，但比较每种药物细胞毒性作用的数据很少。我们发现，PB在体外比PA更具效力；在针对所研究的每个人前列腺癌系的临床可达到剂量下，PB在抑制生长和诱导程序性细胞死亡方面的活性比PA高1.5至2.5倍。PB与丁酸钠等效，丁酸钠可通过多种机制诱导细胞凋亡和分化。前列腺癌细胞系暴露于PB会降低其DNA合成，导致基因组DNA片段化，并使50%至60%的细胞发生凋亡。这些PB诱导的效应比对照或PA的效应大2至10倍。在相似浓度下，丁酸钠可观察到典型的凋亡变化，但PA则不会。过表达P-糖蛋白或具有包括p53突变在内的异质性分子改变的前列腺癌细胞系，对PB的作用也敏感。在体内，口服PB治疗的哥本哈根大鼠，其雄激素抵抗性Dunning R-3327 MAT-LyLu前列腺癌亚系的生长以剂量依赖性方式延迟了30%至45%。这些结果表明，PB除具有分化特性外，还可通过诱导人前列腺癌细胞凋亡发挥细胞毒性作用。
