Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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5-Day Repeated Intravenous Dose Toxicity Study of a New Camptothecin Anticancer Agent CKD-602 in Rats

  • Published : 2004.03.01
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Abstract

The present study was carried out to investigate the potential adverse effects of CKD-602 by a 5-day repeated intravenous dose in Sprague-Dawley rats. The test article, CKD-602, was administered intravenously to male and female rats at dose levels of 0.07, 0.22, 0.67, 2.0 and 6.0 mg/kg/day for 5 days consecutively. Mortalities, clinical findings, and body weight changes were monitored for the 14-day period after cessation of the administration. At the end of 14-day observation period, all animals were sacrificed and complete gross postmortem examinations were performed. There were 2 and 5 treatment related deaths in the 0.67 and 2.0 mg/kg/day dose groups of both genders, respectively. Treatment related clinical signs, including hair loss, skin paleness, decreased locomotor activity, emaciation, and changes in stool were observed in a dose-dependent manner from the third day after initiation of the injection. Decrease or suppression of body weight was also observed dose-dependently in males and females of the treated groups. Gross postmortem examinations revealed a dose-dependent increase in the incidence and severity of atrophy or hypertrophy and white membrane formation in the spleen, atrophy of the thymus, diffuse white spots and paleness of the liver, paleness of the lung, kidney and adrenal gland, and dark red discoloration and dark red contents in the alimentary tract. Based on these results, it was concluded that the 5-repeated intravenous injection of CKD-602 to male and female rats resulted in increased incidence of abnormal clinical signs and death, decreased or suppressed body weight, and increased incidence of abnormal gross findings. In the present experimental conditions, the $LD_{50}$ value was 2.07 (95% confidence limit not specified) mg/kg/day in both genders and the $LD_{10}$ value was 1.72 (95% confidence limit not specified) mg/kg/day in both genders.

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References

  1. Bleiberg, H. and Rothenberg, M.L. (1996): CPT-11: From DNA topology to clinical activity, Semi. Oncol., 23, 1-50
  2. Dahut, W., Harolod, N., Takimototo, C., Allegra, C., Chen, A., Hamilton, J.M., Arbuck, S., Sorensen, M., Grollman, F., Nakashima, H., Lieberman, R., Liang, M., Corse, W. and Grem, J. (1996): Phase I and pharmacokinetic study of 9-aminocamptothecin given as a 72-hour infusion in adult cancer patients, J. Clin. Oncol., 14, 1236-1244
  3. Gottlieb, J.A., Guarino, A.M., Call, J.B., Oliverio, V.T. and Block, J.B. (1970): Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC 100880), Can-cer Chemother. Rep., 54, 461-470
  4. Hashimoto, H., Chatterjee, S. and Berger, N.A. (1995): Muta-genic activity of topoisomerase I inhibitors, Clin. Cancer Res., 1, 369-376
  5. Hertzberg, R.P., Caranfa, M.J., Holden, K.G., Jakas, D.R., Gallagher, G., Mattern, M.R., Mong, S.M., Bartus, J.O., 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
  6. Kim, J.H., Lee, S.K., Lim, J.L., Shin, H.J. and Hong, C.l. (2002): Preformulation studies of a novel camptothecin anticancer agent, CKD-602: physicochemical characteriza-tion and hydrolytic equilibrium kinetics, Int. J. Pharm., 239, 207-211
  7. Kim, E.J., Lee, R.K., Suh, J.E., Han, S.S. and Kim, J.K. (2003a): Safety pharmacology of CKD-602, a novel anti-cancer agent, Arzneimittel Forschung, 53, 272-279
  8. Kim, J.C., Kim, K.H. and Chung, M.K. (1999): Testicular cyto-toxicity of DA-125, a new anthracycline anticancer agent, in rats, Reprod. Toxicol., 13, 391-397
  9. Kim, J.C., Kim, S.H., Shin, D.H., Ahn, T.H., Kim, H.C., Kim, Y.B., Jiang, C.Z., Han, J. and Chung, M.K. (2004): Effects of prenatal exposure to the environmental pollutant 2-bro-mopropane on embryo-fetal development in rats, Toxicol-ogy, 196, 77-86
  10. Kim, J.C., Shin, D.H., Ahn, T.H., Kang, S.S., Song, S.W., Han, J., Kim, C.Y., Ha, C.S. and Chung, M.K. (2003b): 26-Week repeated oral dose toxicity study of the new qui-nolone antibacterial DW-116 in Sprague-Dawley rats, Food Chem. Toxicol., 41, 637-645
  11. Kolimannsberger, C., Mross, K., Jakob, A., Kanz, L. and Boke-myer, C. (1999): Topotecan - A novel topoisomerase I inhibitor: Pharmacology and clinical experience, Oncology, 56, 1-12
  12. 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)- camp-tothecin, CKD602, as a potent DNA topoisomerase I inhibitor, Arch. Pharm. Res., 21, 581-590.
  13. Lee, J.H., Lee, J.M., Lim, K.H., Kim, J.K., Ahn, S.K., Bang, Y.J., and Hong, C.1. (2000): Preclinical and phase I clini-cal studies with CKD-602, a novel camptothecin deriva-tive, Ann. N. Y. Acad. Sci., 922, 324-325
  14. Moertel, C.G., Schutt, A.J., Reitmeier, R.J. and Hahn, R.G. (1972): Phase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinal cancer, Can-cer Chemother. Rep., 56, 95-101
  15. Pizzolato, J.F. and Saltz, L.B. (2003): The camptothecins, Lancet, 361, 2235-2242
  16. Pratesi, G., Tortoreto, M., Corti, C., Giardini, R. and Zunino, F. (1995): Successful local regional therapy with topotecan of intraperitoneally growing human ovarian carcinoma xenografts, Br. J. Cancer. 71, 525-528
  17. SAS Institute, Inc, (1997): SAS/STAT Software: Changes and Enhancements Through Release 6.12. SAS Institute, Cary, NC
  18. Slichenmyer, W.J. and Rowinsky, E.K. (1993): The current status of camptothecin analogues as antitumor agents, J. Natl. Cancer Inst., 85, 271-291 https://doi.org/10.1093/jnci/85.4.271
  19. Song, C.W., Hwang, H.S. and Han, S.S. (1990): Studies on the basic data of Ktc: SD rats with age, Korean J. Lab. Ani. Sci., 6, 33-43
  20. Takimoto, C.H., Wright, J. and Arbuck, S.G. (1998): Clinical applications of the camptothecins, Biochim. Biophys. Acta, 1400, 107-119