Department of Pharmacology and Toxicology, South Valley University, 6 Km, Qena Safaga Road, Qena, Egypt.
Department of Pharmacology and Toxicology, Minia University, Ard Shalaby, Misr-Aswan Road, El-Minia, Egypt.
Biomed Pharmacother. 2017 May;89:36-46. doi: 10.1016/j.biopha.2017.02.019. Epub 2017 Feb 17.
Tubulin targeting agents have received considerable interest as a potential tumor-selective vascular disrupting agents, which represent another avenue for cancer growing therapeutic opportunities. Hence, the present study was conducted to investigate the anti-tumor activity of Combretastatin A-4 phosphate (CA4-P) and vincristine against hepatocellular carcinoma in rats, by individual administration and in combination. In vitro study was conducted using human hepatocellular carcinoma cell lines, showed that CA4-P and vincristine have a potent cell cytotoxic and tubulin inhibitory effect. In addition, a remarkable synergistic effect was observed by the simultaneous application of both drugs. Whereas in vivo study was conducted using model of rat liver cancer initiated with DENA and promoted by CCl, showed that CA4-P and vincristine were significantly decreased liver relative weight, number of hepatic nodules and there relative volumes, tubulin content of the hepatic tissue, GSH and AFP. On the other hand, co-administration of both drugs exhibited significant further decrements in these parameters. Whereas a marked increase in MDA, carbonyl content and TNF-α inside hepatic tissue were observed in the treated groups and these increments were more prominent by co-administration of both drugs. In conclusion CA4-P showed a potential anti-cancer activity against hepatocellular carcinoma and this effect was greatly enhanced by co-administration with vincristine. Additionally, our new findings provided an important evidence that the anticancer activity of drugs with a narrow therapeutic window such as vincristine can be greatly improved by its co-administration with CA4-P providing more enhanced activity with less side effects.
微管靶向剂作为潜在的肿瘤选择性血管破坏剂受到了相当大的关注，这为癌症治疗提供了另一种途径。因此，本研究旨在探讨单独和联合使用 Combretastatin A-4 磷酸盐 (CA4-P) 和长春新碱对大鼠肝癌的抗肿瘤活性。体外研究采用人肝癌细胞系进行，结果表明 CA4-P 和长春新碱对细胞具有很强的细胞毒性和微管抑制作用。此外，同时应用这两种药物观察到显著的协同作用。体内研究采用 DENA 起始和 CCl 促进的大鼠肝癌模型进行，结果表明 CA4-P 和长春新碱显著降低了肝相对重量、肝结节数量及其相对体积、肝组织微管含量、GSH 和 AFP。另一方面，两种药物联合应用表现出这些参数的显著进一步降低。在治疗组中观察到肝组织内 MDA、羰基含量和 TNF-α 的显著增加，并且两种药物联合应用时这些增加更为明显。总之，CA4-P 对肝癌具有潜在的抗癌活性，与长春新碱联合应用可显著增强这种作用。此外，我们的新发现提供了重要证据，表明对于治疗窗较窄的药物（如长春新碱），通过与 CA4-P 联合应用可以大大提高其抗癌活性，同时减少副作用。
