Price A, Shi Q, Morris D, Wilcox M E, Brasher P M, Rewcastle N B, Shalinsky D, Zou H, Appelt K, Johnston R N, Yong V W, Edwards D, Forsyth P
Department of Medical Biochemistry, The University of Calgary, Alberta, Canada.
Clin Cancer Res. 1999 Apr;5(4):845-54.
Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliomas. We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were injected s.c. with U87 cells. Tumors were allowed to grow to a size of approximately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to receive either: (a) 100 mg/kg AG3340 in vehicle; or (b) vehicle control (0.5% carboxymethyl cellulose, 0.1% pluronic F68), both given daily i.p. Tumor area was measured twice weekly, and animals were sacrificed when moribund, or earlier if premorbid histology was examined. In vivo inhibition of tumor growth was profound, with AG3340 decreasing tumor size by 78% compared with controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, and AG3340 mice survived 71 days, representing a >2-fold increase in survival associated with tumor growth delay. Histological examination found that AG3340-treated tumors were smaller, had lower rates of proliferation, and significantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tumors were smaller and sampled after a shorter duration of treatment; the changes in proliferation were more marked and occurred earlier than differences in tumor invasion between the two groups. Furthermore, in vitro cell growth was not inhibited at AG3340 concentrations of <1 mM. AG3340 plasma concentrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion. AG3340 markedly increased survival in this in vivo glioma model. Treatment with AG3340 may be potentially useful in patients with malignant gliomas.
合成基质金属蛋白酶（MMP）抑制剂在临床前模型中对多种肿瘤具有活性，但尚未在胶质瘤中进行研究。我们确定了AG3340（一种新型合成MMP抑制剂，对明胶酶的Ki值在低皮摩尔范围内）对SCID-NOD小鼠中人恶性胶质瘤细胞系（U87）生长的影响。将小鼠皮下注射U87细胞。待肿瘤生长至约0.5×0.5 cm大小（约3周后），将小鼠随机分为两组，分别接受：（a）100 mg/kg AG3340溶于溶媒；或（b）溶媒对照（0.5%羧甲基纤维素，0.1%普朗尼克F68），均每日腹腔注射。每周两次测量肿瘤面积，当动物濒死时处死，若进行病前组织学检查则提前处死。AG3340对肿瘤生长的体内抑制作用显著，31天后（此时对照动物被处死），与对照组相比，AG3340使肿瘤大小减小了78%（P<0.01，Wilcoxon检验）。腹腔注射开始后，对照动物存活31天，AG3340处理的小鼠存活71天，这表明与肿瘤生长延迟相关的生存期增加了2倍以上。组织学检查发现，与对照处理的肿瘤相比，AG3340处理的肿瘤更小，增殖率更低，侵袭明显更少。两组均未发现肝或肺转移。在另一项实验中，肿瘤更小且在较短治疗时间后取样；增殖变化更明显且比两组肿瘤侵袭差异出现得更早。此外，AG3340浓度<1 mM时对体外细胞生长无抑制作用。给药后1小时，AG3340的体内血浆浓度范围为67至365 nM。因此，AG3340对胶质瘤肿瘤生长和侵袭产生了显著抑制作用。在该体内胶质瘤模型中，AG3340显著提高了生存期。用AG3340治疗可能对恶性胶质瘤患者有潜在益处。
