Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil.
Cancer Chemother Pharmacol. 2011 Jul;68(1):45-52. doi: 10.1007/s00280-010-1446-2. Epub 2010 Sep 7.
(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a phenstatin analog compound. PHT is a known tubulin inhibitor that has potent cytotoxic activity. In the present study, PHT was synthesized and its antitumor activity was determined using in vitro and in vivo experimental models.
The in vitro cytotoxic activity of the PHT was determined by the MTT assay. The antimitotic and hemolytic effects were determined based on the inhibition of sea urchin embryo development and lysis of mouse erythrocytes, respectively. In vivo antitumor activity was assessed in mice inoculated with sarcoma 180 cells.
In vitro, PHT displayed cytotoxicity in tumor cell lines, showing IC(50) values in the nanomolar range. In addition, it inhibited sea urchin embryo development during all phases examined, first and third cleavage and blastula stage. However, PHT did not induce hemolysis using mouse erythrocytes, suggesting that the cytotoxicity of PHT does not involve membrane damage. The in vivo study demonstrated tumor inhibition rates of 30.9 and 48.2% for PHT at doses of 20 and 40 mg/kg, respectively. In addition, PHT was also able to increase the response elicited by 5-fluorouracil (5-FU) from 33.3 to 55.7%. The histopathological analysis of liver, kidney, and spleen showed that they were just moderately affected by PHT treatment. Neither enzymatic activity of transaminases nor urea levels were significantly affected. Hematological analysis showed leukopenia after 5-FU treatment, but this effect was prevented when 5-FU was combined with PHT.
In conclusion, PHT exhibited in vitro and in vivo antitumor effects without substantial toxicity.
（4-甲氧基苯基）（3,4,5-三甲氧基苯基）甲酮（PHT）是一种苯并噻嗪类似物化合物。PHT 是一种已知的微管抑制剂，具有很强的细胞毒性。在本研究中，合成了 PHT，并通过体外和体内实验模型确定了其抗肿瘤活性。
通过 MTT 测定法测定 PHT 的体外细胞毒性。根据对海胆胚胎发育的抑制作用和对小鼠红细胞的溶解作用，确定抗有丝分裂和溶血作用。在接种肉瘤 180 细胞的小鼠中评估体内抗肿瘤活性。
体外，PHT 在肿瘤细胞系中表现出细胞毒性，IC50 值在纳摩尔范围内。此外，它在所有检查的阶段，即第一次和第三次卵裂和囊胚阶段，都抑制了海胆胚胎的发育。然而，PHT 对小鼠红细胞没有诱导溶血作用，表明 PHT 的细胞毒性不涉及膜损伤。体内研究表明，PHT 在 20 和 40mg/kg 剂量下，肿瘤抑制率分别为 30.9%和 48.2%。此外，PHT 还能够将 5-氟尿嘧啶（5-FU）引起的反应从 33.3%提高到 55.7%。肝、肾和脾的组织病理学分析表明，它们仅受到 PHT 治疗的中度影响。转氨基酶的酶活性或尿素水平均无明显变化。血液学分析显示，5-FU 治疗后出现白细胞减少，但当 5-FU 与 PHT 联合使用时，可预防这种作用。
总之，PHT 表现出体外和体内抗肿瘤作用，而没有明显的毒性。
