Single dose toxicity study of CKD-602, a new camptothecin anticancer agent, in Beagle dogs

개에서 새로운 캄토테신계 항암제 CKD-602의 단회투여독성시험

  • 김종춘 (전남대학교 수의과대학) ;
  • 신동호 (전남대학교 수의과대학) ;
  • 박승춘 (경북대학교 수의과대학) ;
  • 손우찬 ;
  • 차신우 (한국화학연구원 부설 안전성평가연구소) ;
  • 한정희 (한국화학연구원 부설 안전성평가연구소) ;
  • 배주현 (한국화학연구원 부설 안전성평가연구소) ;
  • 서정은 (한국화학연구원 부설 안전성평가연구소) ;
  • 정문구 (한국화학연구원 부설 안전성평가연구소)
  • Accepted : 2004.03.04
  • Published : 2004.03.31


The present study was carried out to investigate the potential acute toxicity of CKD-602 by a single intravenous dose in Beagle dogs. The test chemical was administered intravenously to male and female Beagle dogs at dose levels of 0.3, 0.5, or 2.5 mg/kg. Mortalities, clinical findings, and body weight changes were monitored for the 14-day period following the administration. At the end of 14-day observation period, all animals were sacrificed and complete gross postmortem examinations were performed. All males and females of the 2.5 mg/kg dose group were found dead between the fourth and seventh day after the injection. Treatment related clinical signs, including vomiting, anorexia, mucous stool, diarrhea, and no stool were observed. Decrease or suppression of body weight was observed in a dose-dependent manner. In autopsy, dark red discoloration of the gastrointestinal tract, atrophy of the thymus, paleness of the spleen, sporadic dark red spots of the lung and petechia of the heart were observed in dead animals of the 2.5 mg/kg dose group. There were no specific adverse effects on males and females of the 0.3 and 0.5 mg/kg dose groups, except for the transient clinical signs such as anorexia, vomiting, and mucus/no stool. On the basis of the results, it was concluded that a single intravenous injection of CKD-602 to Beagle dogs resulted in increased incidence of abnormal clinical signs and death, decreased body weight, and increased incidence of abnormal gross findings. The absolute toxic dose of this chemical was 2.5 mg/kg for both genders. The $LD_{50}$ value was 1.1 mg/kg (95% confidence limit not specified) for both genders. The no-observed-effect level (NOEL) was considered to be below 0.3 mg/kg for both genders.


  1. Bleiberg, H. and Rothenberg, M. L. CPT-11: From DNA topology to clinical activity. Semin. Oncol. 1996, 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. Phase I and pharmacokinetic study of 9-aminocamptothecin given as a 72-hour infusion in adult cancer patients. J. Clin.Oncol. 1996, 14, 1236-1244
  3. Gottlieb, J. A., Guarino, A., Call, J. B., Oliverio, V. T. and Block, J. B. Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC100880). Cancer Chemother. Rep. 1970, 54, 461-470
  4. Hashimoto, H., Chatterjee, S. and Berger, N. A. Mutagenic activity of topoisomerase I inhibitors. Clin. Cancer Res. 1995, 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. Modification of the hydroxy lactone ring of camptothecin: Inhibition of mammalian topoisomerase I and biological activity. J. Med. Chem. 1989, 32, 715-720
  6. Iyer, L. and Ratain, M. J. Clinical pharmacology of camptothecins. Cancer Chemother. Pharmacol. 1998, 42, S31-S43
  7. KFDA. Guidelines for Toxicity Studies of Drugs. Notification No. 1999-61, Korea Food and Drug Administration, Seoul, 1999
  8. Kim, E. J., Lee, R. K., Suh, J. E., Han, S. S. and Kim, J. K. Safety pharmacology of CKD-602, a novel anticancer agent. Arzneimittel forschung. 2003, 53, 272-279
  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. Effects of prenatal exposure to the environmentalpollutant 2-bromopropane on embryo-fetal development in rats. Toxicology. 2004, 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. 26-Week repeated oral dose toxicitystudy of the new quinolone antibacterial DW-116 in Sprague-Dawley rats. Food Chem. Toxicol. 2003, 41, 637-645
  11. Kim, J. H., Lee, S. K., Lim, J. L., Shin, H. J. and Hong, C. I. Preformulation studies of a novel camptothecin anticancer agent, CKD-602: physicochemicalcharacterization and hydrolytic equilibrium kinetics. Int. J. Pharm. 2002, 239, 207-211
  12. Kolimannsberger, C., Mross, K., Jakob, A., Kanz, L. and Bokemyer, C. Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999, 56, 1-12
  13. 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. Antitumor activity of 7-[2-(N-isopropylamino) ethyl]-(20S)-camptothecin, CKD602, as a potent DNA topoisomerase I inhibitor. Arch. Pharm. Res. 1998, 21, 581-590
  14. Lee, J. H., Lee, J. M., Lim, K. H., Kim, J. K., Ahn, S. K., Bang, Y. J. and Hong, C. I. Preclinical and phase I clinical studies with CKD-602, a novel camptothecin derivative. Ann. N. Y. Acad. Sci. 2000, 922, 324-325
  15. Moertel, C. G., Schutt, A. J., Reitmeier, R. J. and Hahn, R. G. Phase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinalcancer. Cancer Chemother. Rep. 1972, 56, 95-101
  16. OECD. Guidelines for the testing of chemicals. No. 401: Acute Oral Toxicity, aris, Organisation for Economic Co-operation and Development. Adopted 24Feb. 1987
  17. Ogawa, M. Novel anticancer drugs in Japan. J. Cancer Res. Clin. Oncol. 1999, 125, 134-140
  18. O'Leary, J. and Muggia, F. M. Camptothecins: a Review of their development and schedules of administration. Eur. J. Cancer. 1998, 34, 1500-1508
  19. Pizzolato, J. F. and Saltz, L. B. The camptothecins. Lancet. 2003, 361, 2235-2242
  20. Pratesi, G., Tortoreto, M., Corti, C., Giardini, R. and Zunino, F. Successful local regional therapy with topotecan of intraperitoneally growing human ovariancarcinoma xenografts. Br. J. Cancer. 1995, 71, 525-528
  21. Slichenmyer, W. J. and Rowinsky, E. K. The current status of camptothecin analogues as antitumor agents. J. Natl. Cancer Inst. 1993, 85, 271-291
  22. Takimoto, C. H., Wright, J. and Arbuck, S. G. Clinical applications of the camptothecins. Biochim. Biophys. Acta. 1998, 1400, 107-119
  23. The european agency for evaluation of medicinal products. CPMP/709/96, Committee for proprietary medicinal products european public assessment report(EPAR), HYCAMTIN International Non-proprietary Name (INN): Topotecan (Abstract), 1996