羊角棉总生物碱增强氟尿嘧啶对结直肠癌化疗敏感性

doi:10.6040/j.issn.1671-7554.0.2024.0261

摘要/Abstract

摘要： 目的观察羊角棉总生物碱在结直肠癌治疗中对氟尿嘧啶(5-fluorouracil, 5-FU)的增敏作用,探讨其对5-FU药代动力学的影响。方法 CCK-8法评价羊角棉总生物碱与5-FU联用对HCT15人结直肠腺癌细胞和CT26.WT小鼠结肠癌细胞杀伤能力;构建小鼠皮下瘤模型,观察5-FU和羊角棉总生物碱单用或联用时对肿瘤生长的影响;LC-MS/MS法检测5-FU及其代谢物二氢氟尿嘧啶(dihydrofluorouracil, FUH₂)和氟脱氧尿苷(fluorodeoxyuridine, FUrd)在大鼠体内的药代动力学参数。结果羊角棉总生物碱对HCT15和CT26.WT细胞毒性的IC₅₀值分别为31.98 μg/mL和23.71 μg/mL;低剂量(100 mg/kg)和高剂量(200 mg/kg)羊角棉总生物碱联用5-FU对荷瘤小鼠的抑瘤率从50.91%分别增长至58.56%和62.16%;5-FU联用羊角棉总生物碱后,T_1/2显著延长,其代谢产物FUrd血药浓度显著下降。结论羊角棉总生物碱对结直肠癌细胞有一定的细胞毒性,与5-FU联用可显著增强其抗结直肠癌活性;羊角棉总生物碱可能通过降低二氢尿嘧啶脱氢酶浓度延缓5-FU分解代谢并调节其合成代谢途径,从而加强其生物学活性。

关键词: 羊角棉, 结直肠癌, 生物碱, 氟尿嘧啶, 细胞毒

Abstract: Objective To observe the sensitizing effect of Alstonia mairei total alkaloids on 5-fluorouracil(5-FU)in the treatment of colorectal cancer, and to explore the influence on the pharmacokinetics of 5-FU. Methods The cytotoxicity of Alstonia mairei total alkaloids combined with 5-FU on HCT15 human colorectal adenocarcinoma cells and CT26.WT mouse colon cancer cells was evaluated by CCK-8 kit. A mouse subcutaneous tumor model was established to observe the effects of 5-FU and Alstonia mairei total alkaloids on tumor growth when used alone or in combination. The pharmacokinetic parameters of 5-FU and its metabolites dihydrofluorouracil(FUH₂)and fluorodeoxyuridine(FUrd)in rats were determined by LC-MS/MS. Results The IC₅₀ values of Alstonia mairei total alkaloids on HCT15 and CT26.WT cells were 31.98 μg /mL and 23.71 μg /mL, respectively. The tumor inhibition rate of low dose(100 mg/kg)and high dose(200 mg/kg)Alstonia mairei total alkaloids combined with 5-FU in tumor-bearing mice increased from 50.91% to 58.56% and 62.16%, respectively. The T_1/2 of 5-FU combined with Alstonia mairei total alkaloids was significantly prolonged, and the plasma concentration of FUrd was significantly decreased. Conclusion The Alstonia mairei total alkaloids have certain cytotoxicity against colorectal cancer cells, and its anti-colorectal cancer activity can be significantly enhanced in combination with 5-FU. Alstonia mairei total alkaloids may enhance the biological activity of 5-FU by reducing the concentration of DPD to delay the catabolism of 5-FU and regulate its anabolic pathway.

Key words: Alstonia mairei, Colorectal cancer, Alkaloids, 5-Fluorouracil, Cytotoxicity

中图分类号:

R574

王潇,孔文茹,崔伟亮,王姝麒. 羊角棉总生物碱增强氟尿嘧啶对结直肠癌化疗敏感性[J]. 山东大学学报 (医学版), 2024, 62(6): 30-37.

WANG Xiao, KONG Wenru, CUI Weiliang, WANG Shuqi. Alstonia mairei total alkaloids enhance the sensitivity of colorectal cancer to 5-fluorouracil chemotherapy[J]. Journal of Shandong University (Health Sciences), 2024, 62(6): 30-37.

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