Rao C V, Tokumo K, Rigotty J, Zang E, Kelloff G, Reddy B S
Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Cancer Res. 1991 Sep 1;51(17):4528-34.
The chemopreventive action of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, D,L-alpha-difluoromethylornithine (DMFO), 16 alpha-fluoro-5-androsten-17-one (DHEA analogue 8354), and ellagic acid (EA) administered in diet individually and in combination before and during initiation and postinitiation phases of azoxymethane-induced neoplasia of the intestine was studied in male F344 rats. The MTD levels of piroxicam, DFMO, DHEA analogue, and EA were determined in male F344 rats and found to be 500, 5,000, 500, and 10,000 ppm, respectively, in modified AIN-76A diet. When these agents were fed in combination, the MTD levels were: piroxicam plus DFMO, 250 and 2500 ppm; piroxicam plus DHEA analogue, 250 and 250 ppm; piroxicam plus EA, 250 and 5000 ppm; piroxicam plus DFMO plus DHEA analogue, 250, 2500, and 250 ppm; and piroxicam plus DFMO plus EA, 250, 2500, and 5000 ppm. From these MTD values, 40 and 80% MTD levels were calculated and tested for their efficacy. At 5 weeks of age, animals were fed the modified AIN-76A (control) diet and experimental diets containing 40 and 80% MTD levels of piroxicam, DFMO, DHEA analogue, and EA individually and in combination. At 7 weeks of age, all animals except the vehicle-treated groups were administrated s.c. injections of azoxymethane (15 mg/kg body weight/week for 2 weeks). Animals intended for vehicle treatment received s.c. injections of an equal volume of normal saline. Fifty-two weeks after azoxymethane and saline treatment all the animals were necropsied, and colon and small intestinal tumor incidence (percentage of animals with tumors) and multiplicity (tumors/animal) were compared among various dietary groups. The results indicate that 40 and 80% MTD levels of dietary piroxicam and DFMO significantly (P less than 0.001) inhibited colon and small intestinal tumor incidence and multiplicity. DHEA analogue at 40% MTD level significantly decreased the small intestinal and colon tumor incidences (P less than 0.05), whereas 80% MTD of DHEA analogue inhibited only small intestinal tumor incidence. EA at 40 and 80% MTDs had no significant effect on colon tumor incidence (P greater than 0.05), but 80% MTD of EA showed a significant inhibitory effect on the incidence of small intestinal adenocarcinomas (P less than 0.01). In the combination study, 40 and 80% MTD levels of piroxicam plus DFMO significantly (P less than 0.001) inhibited colon adenocarcinoma incidence (8.3%) and multiplicity (0.08 +/- 0.04) (SE) when compared to colon adenocarcinoma incidence (72.2%) and multiplicity (1.14 +/- 0.18) in control diet-fed animals.(ABSTRACT TRUNCATED AT 400 WORDS)
在雄性F344大鼠中，研究了在乙基亚硝基脲诱导的肠道肿瘤发生起始期及起始后期之前和期间，饮食中单独及联合给予40%和80%最大耐受剂量（MTD）水平的吡罗昔康、D，L-α-二氟甲基鸟氨酸（DMFO）、16α-氟-5-雄甾烯-17-酮（DHEA类似物8354）和鞣花酸（EA）的化学预防作用。测定了雄性F344大鼠中吡罗昔康、DFMO、DHEA类似物和EA的MTD水平，发现在改良的AIN-76A饮食中分别为500、5000、500和10000 ppm。当这些药物联合喂食时，MTD水平分别为：吡罗昔康加DFMO，250和2500 ppm；吡罗昔康加DHEA类似物，250和250 ppm；吡罗昔康加EA，250和5000 ppm；吡罗昔康加DFMO加DHEA类似物，250、2500和250 ppm；以及吡罗昔康加DFMO加EA，250、2500和5000 ppm。根据这些MTD值，计算出40%和80% MTD水平并测试其功效。5周龄时，给动物喂食改良的AIN-76A（对照）饮食以及含有40%和80% MTD水平的吡罗昔康、DFMO、DHEA类似物和EA单独及联合的实验饮食。7周龄时，除赋形剂处理组外的所有动物皮下注射乙基亚硝基脲（15 mg/kg体重/周，共2周）。用于赋形剂处理的动物皮下注射等体积的生理盐水。乙基亚硝基脲和生理盐水处理52周后，对所有动物进行尸检，比较不同饮食组的结肠和小肠肿瘤发生率（有肿瘤动物的百分比）和多发性（肿瘤/动物）。结果表明，饮食中40%和80% MTD水平的吡罗昔康和DFMO显著（P<0.001）抑制结肠和小肠肿瘤发生率及多发性。40% MTD水平的DHEA类似物显著降低小肠和结肠肿瘤发生率（P<0.05），而80% MTD的DHEA类似物仅抑制小肠肿瘤发生率。40%和80% MTD的EA对结肠肿瘤发生率无显著影响（P>0.05），但80% MTD的EA对小肠腺癌发生率有显著抑制作用（P<0.01）。在联合研究中，与对照饮食喂养动物的结肠腺癌发生率（72.2%）和多发性（1.14±0.18）相比，40%和80% MTD水平的吡罗昔康加DFMO显著（P<0.001）抑制结肠腺癌发生率（8.3%）和多发性（0.08±0.04）（标准误）。（摘要截断于400字）
