Adam L, Crépin M, Isräel L
Institut d'Oncologie Moléculaire et Cellulaire Humaine, Bobigny, France.
Cancer Res. 1997 Mar 15;57(6):1023-9.
We demonstrated previously the antitumoral and antiproliferative effects of sodium phenylacetate (NaPA) on malignant breast epithelial MCF-7ras cells and its lack of toxicity. The present in vivo protocols were as follows: (1) a control group; (2) a NaPA-receiving group (450 mg/kg) through s.c. osmotic pumps (ALZA Corp.) for 2 weeks, followed by 2 weeks with no treatment; and (3) a tamoxifen (TAM)-receiving group (20 mg/kg two times per week). The second group was further divided as follows: (a) a group receiving same doses of NaPA; (b) a TAM-receiving group; and (c) a group receiving both NaPA and TAM. Although tumors treated by TAM alone (group 3) showed progressive regrowth after 6 weeks, indicating an escape from antiestrogen inhibition, the TAM-administered group, following 2 weeks of NaPA pretreatment (group 2b), showed significant tumor regression of about 40% after 8 weeks. This effect was amplified to over 60% (P < 0.001) by simultaneous administration of the two drugs (group 2c). The last group displayed about 30% apoptotic-like nuclei, together with lower proliferation index, and less tumor vascularization, as compared to less than 5% terminal deoxytransferase-mediated dUTP-X nick end labeling-positive nuclei, highly vascularized tumors, in the TAM-treated group. Furthermore, in vitro administration of 4-OH-tamoxifen induced a Bcl-2 up-regulation in MCF-7ras cells, which was completely abolished by NaPA pretreatment. The combination of NaPA and OHT induced significant cell differentiation with cell cycle accumulation in the G0-G1 phase.
我们之前已证明苯乙酸钠（NaPA）对恶性乳腺上皮MCF-7ras细胞具有抗肿瘤和抗增殖作用，且无毒性。目前的体内实验方案如下：（1）对照组；（2）通过皮下渗透泵（ALZA公司）给予NaPA的组（450 mg/kg），持续2周，随后2周不进行治疗；（3）接受他莫昔芬（TAM）的组（20 mg/kg，每周两次）。第二组进一步分为：（a）接受相同剂量NaPA的组；（b）接受TAM的组；（c）同时接受NaPA和TAM的组。尽管单独用TAM治疗的肿瘤（第3组）在6周后显示出逐渐复发，表明逃脱了抗雌激素抑制，但在NaPA预处理2周后给予TAM的组（第2b组）在8周后显示出约40%的显著肿瘤消退。两种药物同时给药（第2c组）使这种效果放大至超过60%（P < 0.001）。与TAM治疗组中不到5%的末端脱氧核苷酸转移酶介导的dUTP-X缺口末端标记阳性细胞核、高度血管化的肿瘤相比，最后一组显示出约30%的凋亡样细胞核，同时增殖指数较低，肿瘤血管化程度较低。此外，体外给予4-羟基他莫昔芬可诱导MCF-7ras细胞中Bcl-2上调，而NaPA预处理可完全消除这种上调。NaPA和OHT的联合使用诱导了显著的细胞分化，并使细胞周期停滞在G0-G1期。
