Ouyang Nengtai, Williams Jennie L, Tsioulias George J, Gao Jianjun, Iatropoulos Michael J, Kopelovich Levy, Kashfi Khosrow, Rigas Basil
Division of Cancer Prevention, State University of New York at Stony Brook, Stony Brook, New York 11794-5200, USA.
Cancer Res. 2006 Apr 15;66(8):4503-11. doi: 10.1158/0008-5472.CAN-05-3118.
To evaluate the chemopreventive effect of nitric oxide-donating aspirin (NO-ASA), an ASA bearing a NO-releasing moiety, against pancreatic cancer, we studied six groups of female Syrian golden hamsters: groups 1 to 3 (n = 12 each) were given saline and groups 4 to 6 (n = 17) the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in five weekly injections (the first, 70 mg/kg, and the remaining, 20 mg/kg each). Control and BOP-treated hamsters were fed a NO-ASA 3,000 ppm or conventional ASA 3,000 ppm or control diet for 19 weeks. Groups 1 to 3 had no tumors. Compared with the BOP/vehicle group, NO-ASA reduced the incidence (88.9%, P < 0.003) and multiplicity (94%, P < 0.05) of pancreatic cancer; ASA had no statistically significant effect. NO-ASA arrested the transition from PanIN2 to PanIN3 and carcinoma. The proliferation (proliferating cell nuclear antigen) / apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling) ratio of ductal cells increased with the histologic severity of the ductal lesion; NO-ASA suppressed it significantly during all stages except PanIN1A. p21(WAF1/CIP1), undetectable in normal cells, was progressively induced in neoplastic cells and suppressed by NO-ASA up to PanIN3. Nuclear factor-kappaB activation, absent in normal tissue, increased progressively (17-fold in cancer); NO-ASA suppressed it throughout and significantly in PanIN1B and PanIN2. Cyclooxygenase-2 expression, absent during early stages, was induced 6-fold in carcinoma and suppressed by NO-ASA in PanIN3 and carcinoma. Conventional ASA had no effect on these molecular markers. Thus, NO-ASA profoundly prevented pancreatic cancer and modulated multiple molecular targets in this model system; conventional ASA had no such effects. NO-ASA merits further evaluation as a chemopreventive agent against pancreatic cancer.
为评估携带一氧化氮释放基团的阿司匹林（NO-ASA）对胰腺癌的化学预防作用，我们研究了六组雌性叙利亚金仓鼠：第1至3组（每组n = 12）给予生理盐水，第4至6组（n = 17）皮下注射致癌物N-亚硝基双（2-氧代丙基）胺（BOP），每周注射五次（第一次70 mg/kg，其余每次20 mg/kg）。对照和BOP处理的仓鼠分别喂食含3000 ppm NO-ASA或3000 ppm传统阿司匹林或对照饮食19周。第1至3组无肿瘤。与BOP/赋形剂组相比，NO-ASA降低了胰腺癌的发病率（88.9%，P < 0.003）和多灶性（94%，P < 0.05）；阿司匹林无统计学显著作用。NO-ASA阻止了从胰腺上皮内瘤变2级（PanIN2）到胰腺上皮内瘤变3级（PanIN3）以及癌的转变。导管细胞的增殖（增殖细胞核抗原）/凋亡（末端脱氧核苷酸转移酶介导的缺口末端标记）比值随导管病变的组织学严重程度增加；NO-ASA在除PanIN1A之外的所有阶段均显著抑制该比值。p21（WAF1/CIP1）在正常细胞中不可检测，在肿瘤细胞中逐渐诱导产生，并被NO-ASA抑制至PanIN3阶段。核因子-κB活化在正常组织中不存在，在癌症中逐渐增加（癌症中增加17倍）；NO-ASA在整个过程中均抑制其活化，在PanIN1B和PanIN2中显著抑制。环氧合酶-2表达在早期不存在，在癌中诱导增加6倍，并被NO-ASA在PanIN3和癌中抑制。传统阿司匹林对这些分子标志物无作用。因此，在该模型系统中，NO-ASA可显著预防胰腺癌并调节多个分子靶点；传统阿司匹林则无此作用。NO-ASA作为胰腺癌化学预防剂值得进一步评估。
