Previous studies have demonstrated that CW252053, a quinazoline antifolate, exhibits potent inhibitory activity against thymidylate synthase (TS) as well as cytotoxic activity against tumor cell linesin vitro. In this study, we evaluated thein vivo antitumor efficacy of CW252053 in the mouse tumor model. Female B6D2F1 mice were injected with LY3.7.2C TK-/- (thymidine kinase deficient mouse lymphoma) cells into the gastrocnemius muscle. Then, CW252053 was administered twice daily by intraperitoneal injection for 10 days, and tumor growth was monitored daily by leg diameter measurement. All animals in the vehicle, 5-FU, and low dose (30 mg/kg) CW252053 treated groups died between days 12 and 23 because of the tumor burden. In contrast, dosing with 60 mg/kg of CW252053 produced a cure rate against tumor growth of 37.5% and a survival rate of 50%. Even more significantly, a higher dose of CW252053 (120 mg/kg) elicited both a 100% cure rate and a 100% survival rate at the termination of the study, confirming that this compound has very potentin vivo antitumor activity against tumor growth. During the experimental period of this study no signs of toxicity were observed even at the high CW252053 dosage rate of 120 mg/kg.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Appelt, K., Bacquet, R.J., Bartlett, C. A., Booth, C. L. J., Freer, S. T., Fuhry, M. A. M., Cehring, M. R., Herrmann, S. M., Howland, E. F., Janson, C. A., Jones, T. R., Kan, C. -C., Kathardekar, V., Lewis, K. K., Marzoni, C. R., Matthews, D. A., Mohr, C., Moomaw, E. W., Morse, C. A., Oatley, S. J., Ogden, R. C., Reddy, M. R., Reich, S. H., Schoettlin, W. S., Smith, W. W., Varney, M. D., Villafranca, J. E., Ward, R. W., Webber, S., Webber, S. E., Welsh, K. M., and White, J., Design of enzyme inhibitors using iterative protein crystallographic analysis.J. Med. Chem., 34, 1925–1934 (1991).
Baek, D. -J., Park, Y. -K., Heo, H. I., Lee, M., Yang, Z., and Choi, M., Synthesis of 5-substituted quinazoline derivatives and their inhibitory activityin vitro.Bioorg. Med. Chem. Lett., 8, 3287–3290 (1998).
Jackman, A. L., Kimbell, R., Brown, M., Brunton, L., Harrap, K. R., Wardelworth, J. M., and Boyle, F. T., The antitumour activity of ZD9331, a non-polyglutamatable quinazoline thymidylate synthase inhibitor.Adv. Exp. Med. Biol., 370, 185–188 (1994).
Johnston, R. C., Liang, C. M., Henry, S., Chabner, B. A., and Allegra, C. J., Production and characterization of monoclonal antibodies that localize human thymidylate synthase in the cytoplasm of human cells and tissue.Cancer Res., 51, 6668–6676 (1991).
Johnston, R. C., Drake, J. C., Steinberg, S. M., and Allegra, C. J., Quantitation of thymidylate synthase in human tumors using an ultrasensitive enzyme-linked immunoassay.Biochem. Pharmacol., 45, 2483–2486 (1993).
Jones, T. R., Calvert, A. H., Jackman, A. L., Brown, S. J., Jones, M., and Harrap, K. R., A potent antitumour quinazoline inhibitor of thymidylate synthetase: synthesis, biological properties and therapeutic results in mice.Europ. J. Cancer., 17, 11–19 (1981).
Stephens, T. C., Smith, M. N., Waterman, S. E., McCloskey, M. L., Jackman, A. L., and Boyle, F. T., Use of murine L5178Y lymphoma thymidine kinase mutants forin vitro andin vivo antitumour efficacy evaluation of novel thymidylate synthase inhibitors.Adv. Exp. Med. Biol., 338, 589–592 (1993).
Takemura, Y. and Jackman, A. L., Folate-based thymidylate synthase inhibitors in cancer chemotherapy.Anti-Cancer Drugs, 8, 3–16 (1997).
Walton, M. I., Gibson, W., Aherne, G. W., Lawrence, N., Stephens, T. C., Smith, M. N. and Jackman, A. L., Preclinical pharmacology of CB30900, a novel dipeptide inhibitor of thymidylate synthase, in mice.J. Pharmacol. Exp. Ther., 277, 909–916 (1996).
Webber, S., Bartlett, C. A., Boritzki, I. J., Hilliard, J. A., Howland, E. F., Johnston, A. L., Kosa, M., Margosiak, S. A., Morse, C. A., and Shetty, B. A., AG337, a novel lipophilic thymidylate synthase inhibitor:in vitro andin vivo preclinical studies.Cancer Chemother. Pharmacol., 37, 509–517 (1996).
About this article
Cite this article
Oh, S., Ha, J. & Baek, D. In Vivo Antitumor Efficacy of CW252053, A Folate-based Thymidylate Synthase Inhibitor. Arch Pharm Res 24, 323–326 (2001). https://doi.org/10.1007/BF02975100
- Thymidylate synthase (TS) inhibitor
- in vivo antitumor efficacy
- LY3.7.2C TK-/-