Toxicity Study of CKD-602, a Camptothecin Anticancer Agent: 5-Day Repeated Intravenous Administration in Rats

  • Published : 2004.03.01

Abstract

The present study was conducted to investigate the potential subacute toxicity of CKD-602 by a 5-day repeated intravenous administration in Sprague-Dawley rats. CKD-602 was administered intravenously to male rats at dose levels of 0, 0.08, 0.2, and 0.5 mg/kg for 5 days. Studies included general observation, body weight changes, ophthalmoscopic examination, hematology, se겨m biochemistry, gross findings at necropsy and organ weight measurement. There were no deaths in any treatment group and treatment related clinical sign was depilation in the 0.5 mg/kg groups. The decrease or suppression of body weight was also observed dose-dependently in all treatment groups. Decreased leukocyte in all treatment groups, decreased platelet in the above 0.2 mg/kg groups and increase in the serum levels of total cholesterol in the 0.5 mg/kg group were considered as a treatment related toxic effects. Decreased weight of thymus in all treatment groups anti decreased weight of spleen in the above 0.2 mg/kg group were observed. The intravenous administration of CKD-602 caused depilation and decreased weight and had toxic effect on the leukocyte, platelet, spleen and thymus. In the condition of this study, the target organs were spleen and thymus and the toxic effect level was determined to be 0.2 mg/kg, but no-observed-adverse-effect level (NOAEL) was considered to be lower than 0.08 mg/kg.

Keywords

References

  1. Han, J., Kim, J.C., Chung, M.K, Kim, B. and Choi, D.R. (2003). Subacute toxicity and toxicokinetics of a new antibiotic, DW-224a, after single and 4-week repeated oral administration in dogs. BioI. Phann. Bull., 26, 832-839 https://doi.org/10.1248/bpb.26.832
  2. Hertzberg, R.P., Caranfa, M.J., Holden, K.G., Jakas, D.R, Gallagher, G., Mattern, M.R., Mong, S.M., Bartus, J.D., Johnson, R.K and Kingsbury, W.D. (1989). Modification of the hydroxy lactone ring of camptothecin: Inhibition of mammalian topoisomerase I and biological activity. J. Med. Chem., 32, 715-720 https://doi.org/10.1021/jm00123a038
  3. Kang, B. H., Son, H. Y., Ha, C. S., Lee, H. S. and Song, S. W.(1995). Reference values of hematology and serum chemistry in Ktc: Sprague-Dawley rats. Korean J. Lab. Ani. Sci., 1, 141-145
  4. Kurita, A., Kado, S., kaneda, N., Onoue, M., Hashimoto, S. and Yokokura, T. (2000). Modified irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayedonset diarrhea in rats. Cancer Chemother Pharmacal., 46, 211-220 https://doi.org/10.1007/s002800000151
  5. Lee, J.H., Lee, J.M., Kim, J.K., Ahn, S.K., Lee, S.J., Kim, M.Y., Jew, S.S., Park, J.G. and Hong, C.I. (1998). Antitumor activity of 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, CKD-602, as a potent DNA topoisomerase I inhibitor. Arch. Pharm. Res., 21, 581-590 https://doi.org/10.1007/BF02975379
  6. Moore, B.G., Schwartz, H.S., and Hodo, H. (1970). Inhibition of macromolecular synthesis in L1210 ascites tumor cells. J. Cell. Bioi., 47, 144A
  7. NRC (National Research Council) (1996). Guide for the Care and Use of Laboratory Animals. National Academy, Washington. Pizzolato, J.E and Saltz, L.B. (2003). The camptothecins. Lancet, 361, 2235-2242 https://doi.org/10.1016/S0140-6736(03)13780-4
  8. Pizzolato, J.F. and Saltz, L.B. (2003). The camptothecins. Lancet, 361, 2235-2242. https://doi.org/10.1016/S0140-6736(03)13780-4
  9. Pratesi, G., Tortoreto, M., Corti, C., Giardini, R. and Zunino, F. (1995). Successful local therapy with topotecan of intraperitoneally growing human ovarian carcinoma xenografts. Br. J. Cancer, 71, 525-528 https://doi.org/10.1038/bjc.1995.104
  10. Prijovich, Z.M., Chen, B.M., Leu, Y.L., Chern, J.W. and Roffler, S.R. (2002). Anti-tumor activity and toxicity of the new prodrug 9-aminocamptothecin glucuronide (9ACG) in mice. Br. J. Cancer, 86, 1634-1638 https://doi.org/10.1038/sj.bjc.6600317
  11. Schaeppi, R.W., Fleischman, R.W. and Cooney, D.A. (1974). Toxicity of Camptothecin (NSC-100880). Cancer Chemother. Rep., 5, 25-36
  12. Wall, M.E., Wani, M.C. and Cook, C.E. (1966). Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J. Am. Chem. Soc., 88, 3888-3890 https://doi.org/10.1021/ja00968a057
  13. Wolford, S. T., Schroer, R. A., Gohs, F. X.., Gallo, P. P., Brodeck, M., Falk, H. B., and Ruhren, F. R. (1986). Reference range data base for serum chemistry and hematology values in laboratory animals. J. Toxicol. Environ. Health 18, 161-188 https://doi.org/10.1080/15287398609530859