Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340

Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliom as, We determined the effect of AG3340, a novel synthetic MMP inhibitor wit h Ki values against gelatinases in the low picomolar range, on the growth o f a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were inje cted s.c. with U87 cells. Tumors were allowed to grow to a size of approxim ately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to r eceive 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 wit h controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, a nd AG3340 mice survived 71 days, representing a >2-fold increase in surviva l associated with tumor growth delay. Histological examination found that A G3340-treated tumors were smaller, had lower rates of proliferation, and si gnificantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tu mors were smaller and sampled after a shorter duration of treatment; the ch anges in proliferation were more marked and occurred earlier than differenc es in tumor invasion between the two groups. Furthermore, in vitro cell gro wth was not inhibited at AG3340 concentrations of <1 mM, AG3340 plasma conc entrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thu s, AG3340 produced a profound inhibition of glioma tumor growth and invasio n. AG3340 markedly increased survival in this in vive glioma model. Treatme nt with AG3340 may be potentially useful in patients with malignant gliomas .