Pili R, Kruszewski M P, Hager B W, Lantz J, Carducci M A
The Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Cancer Res. 2001 Feb 15;61(4):1477-85.
Differentiation-inducing agents, such as retinoids and short-chain fatty acids, have an inhibitory effect on tumor cell proliferation and tumor growth in preclinical studies. Clinical trials involving these compounds as single agents have been suboptimal in terms of clinical benefit. Our study evaluated the combination of phenylbutyrate (PB) and 13-cis retinoic acid (CRA) as a differentiation and antiangiogenesis strategy for prostate cancer. On the basis of previous evidence, common signal transduction pathways and possible modulation of retinoid receptors and retinoid response elements by PB could be responsible for such activities. We assessed the effect of the combination of PB and CRA on human and rodent prostate carcinoma cell lines. The combination of PB and CRA inhibited cell proliferation and increased apoptosis in vitro in an additive fashion as compared with single agents (P < 0.014). Prostate tumor cells treated with both PB and CRA revealed an increased expression of a subtype of retinoic acid receptor (retinoic acid receptor-beta), suggesting a molecular mechanism for the biological additive effect. The combination of PB and CRA also inhibited prostate tumor growth in vivo (up to 82-92%) as compared with single agents (P < 0.025). Histological examination of tumor xenografts revealed decreased in vivo tumor cell proliferation, an increased apoptosis rate, and a reduced microvessel density in the animals treated with combined drugs, suggesting an antiangiogenesis effect of this combination. Thus, endothelial cell treatment with both PB and CRA resulted in reduced in vitro cell proliferation. In vivo testing using the Matrigel angiogenesis assay showed an additive inhibitory effect in the animals treated with a combination of PB + CRA (P < 0.004 versus single agents). In summary, this study showed an additive inhibitory effect of combination of differentiation agents PB and CRA on prostate tumor growth through a direct effect on both tumor and endothelial cells.
在临床前研究中，诸如维甲酸和短链脂肪酸等分化诱导剂对肿瘤细胞增殖和肿瘤生长具有抑制作用。以这些化合物作为单一药物的临床试验在临床获益方面并不理想。我们的研究评估了苯丁酸盐（PB）和13 - 顺式维甲酸（CRA）联合使用作为前列腺癌的分化和抗血管生成策略。基于先前的证据，PB常见的信号转导途径以及对维甲酸受体和维甲酸反应元件的可能调节可能是造成此类活性的原因。我们评估了PB和CRA联合使用对人和啮齿动物前列腺癌细胞系的影响。与单一药物相比，PB和CRA联合使用在体外以相加的方式抑制细胞增殖并增加细胞凋亡（P < 0.014）。同时用PB和CRA处理的前列腺肿瘤细胞显示维甲酸受体的一种亚型（维甲酸受体 - β）表达增加，提示了这种生物学相加效应的分子机制。与单一药物相比，PB和CRA联合使用在体内也抑制前列腺肿瘤生长（高达82 - 92%）（P < 0.025）。对肿瘤异种移植的组织学检查显示，联合用药处理的动物体内肿瘤细胞增殖减少、凋亡率增加且微血管密度降低，提示这种联合具有抗血管生成作用。因此，用PB和CRA处理内皮细胞导致体外细胞增殖减少。使用基质胶血管生成试验的体内测试显示，在接受PB + CRA联合治疗的动物中具有相加的抑制作用（与单一药物相比，P < 0.004）。总之，本研究表明分化剂PB和CRA联合使用通过对肿瘤细胞和内皮细胞的直接作用对前列腺肿瘤生长具有相加的抑制作用。
