Kadhim S A, Bowlin T L, Waud W R, Angers E G, Bibeau L, DeMuys J M, Bednarski K, Cimpoia A, Attardo G
Biochem Therapeutic Inc., Laval, Quebec, Canada.
Cancer Res. 1997 Nov 1;57(21):4803-10.
Beta-L-Dioxolane-cytidine (BCH-4556) is a novel anticancer nucleoside analogue with a stereochemically unnatural beta-L configuration. This compound was previously shown to have a potent antitumor activity in human prostate and hepatocellular xenograft tumor models (K. L. Grove et al., Cancer Res., 55: 3008-3011, 1995). Herein, we extended the efficacy validation of BCH-4556 to renal cell carcinoma (RCC) cell lines both in vitro and in vivo. In vitro cytotoxicity and proliferation inhibition determinations in human RCC cell lines CAKI-1, CAKI-2, 786-0, and A498 produced IC50 concentrations ranging from 15-35 nM. In vivo antitumor activity was consistent with the in vitro sensitivity. BCH-4556 was very effective in human RCC tumor xenograft models, including CAKI-1, A498, RXF-393, and SN12C carcinomas. Very good responses were observed in animals bearing CAKI-1, A498, and RXF-393 RCC tumors given i.p. doses of 10, 25, and 50 mg/kg twice a day for 5 days, with complete regression recorded in most of the animals tested. Curative activity was also observed, with 40-60% of animals remaining tumor free in all three RCC models at the day of study termination. Significant tumor shrinkage was also evident in the SN12C model. BCH-4556 efficacy evaluation in the orthotopic subrenal capsule tumor models demonstrated a potent tumor growth inhibition against human CAKI-1 xenografts and tumor stasis against mouse Renca tumors. BCH-4556 was also effective in inhibiting the growth of rebound CAKI-1 tumors after the administration of a second treatment cycle. The observed antitumor activity of BCH-4556 in several RCC human solid tumor xenografts, including the lethal RXF-393 model, warrants further investigation of this novel nucleoside analogue in clinical trials of RCC.
β-L-二氧戊环胞苷（BCH-4556）是一种新型的抗癌核苷类似物，具有立体化学上非天然的β-L构型。该化合物先前已显示在人前列腺和肝细胞异种移植肿瘤模型中具有强大的抗肿瘤活性（K.L.格罗夫等人，《癌症研究》，55:3008 - 3011，1995）。在此，我们将BCH-4556的疗效验证扩展至肾细胞癌（RCC）细胞系的体外和体内研究。在人RCC细胞系CAKI-1、CAKI-2、786-0和A498中进行的体外细胞毒性和增殖抑制测定产生的IC50浓度范围为15 - 35 nM。体内抗肿瘤活性与体外敏感性一致。BCH-4556在人RCC肿瘤异种移植模型中非常有效，包括CAKI-1、A498、RXF-393和SN12C癌。在腹腔注射剂量为10、25和50 mg/kg，每天两次，共5天的携带CAKI-1、A498和RXF-393 RCC肿瘤的动物中观察到非常好的反应，在大多数测试动物中记录到完全消退。还观察到治愈活性，在研究终止日，所有三个RCC模型中40 - 60%的动物无肿瘤。在SN12C模型中也明显观察到显著的肿瘤缩小。在原位肾包膜下肿瘤模型中对BCH-4556的疗效评估表明，其对人CAKI-1异种移植瘤具有强大的肿瘤生长抑制作用，对小鼠Renca肿瘤具有肿瘤停滞作用。在给予第二个治疗周期后，BCH-4556在抑制CAKI-1肿瘤的反弹生长方面也很有效。BCH-4556在包括致命的RXF-393模型在内的几种RCC人实体肿瘤异种移植瘤中观察到的抗肿瘤活性，值得在RCC临床试验中对这种新型核苷类似物进行进一步研究。
