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Clinical Cancer Research Vol. 5, 845-854, April 1999
© 1999 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Marked Inhibition of Tumor Growth in a Malignant Glioma Tumor Model by a Novel Synthetic Matrix MetalloproteinaseInhibitor AG33401

Angela Price, Qiao Shi, Donald Morris, M. Elizabeth Wilcox, Penny M. A. Brasher, N. Barry Rewcastle, David Shalinsky, Helen Zou, Krzysztof Appelt, Randall N. Johnston, V. Wee Yong, Dylan Edwards2 and Peter Forsyth2,, 3

Departments of Medical Biochemistry and Clinical Neurosciences [A. P., Q. S., M. E. W.], Medical Biochemistry [R. N. J., D. E.], Oncology and Clinical Neurosciences [V. W. Y.], and Clinical Neurosciences and Pediatrics [P. F.], The University of Calgary, Calgary, Alberta, T2N 4N2 Canada; Departments of Medicine [D. M., P. F.] and Epidemiology, Prevention, and Screening [P. M. A. B.], Tom Baker Cancer Centre [A. P., Q. S., M. E. W.], Calgary, Alberta, T2N 4N2 Canada; Pathology Department, Foothills Hospital, Calgary, Alberta, Canada [N. B. R.]; Departments of Pharmacology and Ophthalmology Research, Agouron Pharmaceuticals, Inc., San Diego, California [D. S., H. Z., K. A.]

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.




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