Kassouf Wassim, Highshaw Ralph, Nelkin Gina M, Dinney Colin P, Kamat Ashish M
Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Urol. 2006 Oct;176(4 Pt 1):1642-7. doi: 10.1016/j.juro.2006.06.042.
We evaluated the antitumor effects of vitamins C and K3 for human urothelial carcinoma and the potential use of the combination of vitamins C plus K3 as a sensitizing agent for conventional chemotherapy for urothelial carcinoma.
The antiproliferative and apoptotic effects of vitamin C alone, vitamin K3 alone, vitamins C plus K3, gemcitabine alone and gemcitabine plus vitamins C plus K3 were assessed in vitro by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, propidium iodide staining and flow cytometry. For in vivo studies we implanted UMUC-14 tumorigenic urothelial carcinoma cells into the subcutis of nude mice. One week later we treated 10 mice each with saline (control), vitamins C plus K3, gemcitabine or gemcitabine plus vitamins C plus K3. Treatment was continued for 4 weeks, followed by necropsy. Tumor volume was measured and tumor kinetics were established. Apoptosis and proliferation were evaluated in tumor sections using immunohistochemistry and TUNEL assay.
Vitamins C plus K3 induced cytostasis and caused apoptosis to a greater degree than either vitamin alone (p < 0.05). Vitamins C plus K3 also substantially augmented the effects of gemcitabine in vitro. There were 32.3% apoptosis with gemcitabine plus vitamins C plus K3, 5.3% with gemcitabine alone and 15.8% with vitamins C plus K3 alone (p < 0.05). In vivo tumor growth was substantially inhibited by gemcitabine plus vitamins C plus K3 compared with that in the control or for either agent alone. Mean tumor weight and growth rate in the gemcitabine plus vitamins C plus K3 group (237 mg and 11.3 mm3 daily) were decreased compared with those in the control (530 mg and 34.3 mm3 daily), and those for vitamins C plus K3 alone (490 mg and 25.2 mm3 daily) and gemcitabine alone (400 mg and 21.3 mm3 daily) (p < 0.05).
Vitamins C and K3 have significant antiproliferative and apoptotic effects when used in combination. This combination enhances the efficacy of gemcitabine against bladder cancer in vivo.
我们评估了维生素C和维生素K3对人膀胱尿路上皮癌的抗肿瘤作用，以及维生素C加维生素K3联合作为膀胱尿路上皮癌传统化疗增敏剂的潜在用途。
通过MTT（3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐）法、碘化丙啶染色和流式细胞术在体外评估单独使用维生素C、单独使用维生素K3、维生素C加维生素K3、单独使用吉西他滨以及吉西他滨加维生素C加维生素K3的抗增殖和凋亡作用。对于体内研究，我们将UMUC-14致瘤性膀胱尿路上皮癌细胞植入裸鼠皮下。一周后，我们分别用生理盐水（对照）、维生素C加维生素K3、吉西他滨或吉西他滨加维生素C加维生素K3处理10只小鼠。治疗持续4周，然后进行尸检。测量肿瘤体积并建立肿瘤生长动力学。使用免疫组织化学和TUNEL法在肿瘤切片中评估凋亡和增殖情况。
维生素C加维生素K3诱导细胞生长停滞，且比单独使用任何一种维生素诱导凋亡的程度更大（p < 0.05）。维生素C加维生素K3在体外也显著增强了吉西他滨的作用。吉西他滨加维生素C加维生素K3组的凋亡率为32.3%，单独使用吉西他滨组为5.3%，单独使用维生素C加维生素K3组为15.8%（p < 0.05）。与对照组或单独使用任何一种药物相比，吉西他滨加维生素C加维生素K3在体内显著抑制肿瘤生长。吉西他滨加维生素C加维生素K3组的平均肿瘤重量和生长速率（分别为237 mg和每日11.3 mm³）低于对照组（分别为530 mg和每日34.3 mm³）、单独使用维生素C加维生素K3组（分别为490 mg和每日25.2 mm³）以及单独使用吉西他滨组（分别为400 mg和每日21.3 mm³）（p < 0.05）。
维生素C和维生素K3联合使用具有显著的抗增殖和凋亡作用。这种联合增强了吉西他滨在体内对膀胱癌的疗效。
