McLennan Gordon, Cressman Erik N K, Xu Yonghua, Zhang Dianbo, Jagtap Mandar R, Jayaram Hiremagular N
Department of Radiology, Indiana University Medical Center, Indiana University/Purdue University at Indianapolis, Indianapolis, Indiana, USA.
J Vasc Interv Radiol. 2005 Nov;16(11):1499-504. doi: 10.1097/01.RVI.0000185416.08458.01.
Benzamide riboside (BR) causes apoptosis in multiple tumor cell lines by its inhibition of guanylate biosynthesis. The purpose of this study was to determine the feasibility of the use of BR as a therapeutic agent for hepatic artery infusional cancer therapy in a rabbit VX2 papilloma tumor model.
VX2 tumor was implanted into the left lobe of the liver of each of 14 New Zealand White rabbits and allowed to grow for 19 days +/- 3. The proper hepatic artery was selected with a 3-F catheter via right femoral cutdown. The animals were treated with one infusion of 0.9% saline solution (n = 2), 1 mg/kg BR (n = 4), 5 mg/kg BR (n = 4), or 10 mg/kg BR (n = 4). One animal treated with 5 mg/kg BR did not develop tumor. Livers were explanted after 24 hours and sectioned through the tumor. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed on the slides and they were imaged at a magnification of 40 to detect apoptotic cells. Four random fields were obtained from each slide and the percentage of apoptotic cells was calculated by dividing the number of TUNEL-positive cells by the total number of cells. Sections of liver not involved with tumor were seen in five animals: two that received 1 mg/kg BR, one that received 5 mg/kg, and two that received 10 mg/kg.
The mean tumor apoptosis rates were 1.3% with saline solution treatment, 44.8% with 1 mg/kg BR, 52.7% with 5 mg/kg BR, and 70.7% with 10 mg/kg BR. The mean tumor apoptosis in treated animals was significantly greater than in control animals (P = .003) and mean tumor apoptosis was significantly greater with 10 mg/kg BR than with 1 mg/kg BR (P = .03). There were no apoptotic cells in normal liver treated with 1 mg/kg BR or 10 mg/kg BR. The animal that received 5 mg/kg BR exhibited 10.5% apoptotic cells in the field examined (eight of 76 cells). In the animal treated with 5 mg/kg BR but in which tumor did not grow, only one of 76 cells (0.65%) was apoptotic in the area of the injection scar.
BR induces apoptosis in VX2 tumor in the rabbit model with minimal apoptosis in normal liver.
苯甲酰胺核苷（BR）通过抑制鸟苷酸生物合成，可诱导多种肿瘤细胞系发生凋亡。本研究旨在确定在兔VX2乳头瘤肿瘤模型中，BR作为肝动脉灌注癌症治疗药物的可行性。
将VX2肿瘤植入14只新西兰白兔的肝左叶，使其生长19天±3天。经右股动脉切开，用3F导管选择合适的肝动脉。动物分别接受一次0.9%生理盐水输注（n = 2）、1 mg/kg BR（n = 4）、5 mg/kg BR（n = 4）或10 mg/kg BR（n = 4）治疗。一只接受5 mg/kg BR治疗的动物未发生肿瘤。24小时后取出肝脏，沿肿瘤切片。对切片进行末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色，并以40倍放大倍数成像以检测凋亡细胞。从每张切片中随机获取四个视野，通过将TUNEL阳性细胞数除以细胞总数来计算凋亡细胞百分比。在五只动物中观察到未发生肿瘤的肝脏切片：两只接受1 mg/kg BR，一只接受5 mg/kg，两只接受10 mg/kg。
生理盐水治疗组的平均肿瘤凋亡率为1.3%，1 mg/kg BR组为44.8%，5 mg/kg BR组为52.7%，10 mg/kg BR组为70.7%。治疗动物的平均肿瘤凋亡率显著高于对照动物（P = 0.003），且10 mg/kg BR组的平均肿瘤凋亡率显著高于1 mg/kg BR组（P = 0.03）。接受1 mg/kg BR或10 mg/kg BR治疗的正常肝脏中未发现凋亡细胞。接受5 mg/kg BR治疗的动物在所检查的视野中凋亡细胞占10.5%（76个细胞中有8个）。在接受5 mg/kg BR治疗但肿瘤未生长的动物中，注射瘢痕区域的76个细胞中仅有1个（0.65%）凋亡。
在兔模型中，BR可诱导VX2肿瘤发生凋亡，而对正常肝脏的凋亡影响极小。
