Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지

Comparison of Single-Dose Toxicity by Intravenous Infusion or Bolus Injection with CKD-602, a Camptothecin Anticancer Agent in Rats (I): Toxic Effects with regard to Mortality and Clinical Signs

  • Published : 2004.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

The toxicity of CKD-602 was investigated at doses of 0, 3, 9, and 27 mg/kg in rats, by administering the same total dose over 24-hr continuous infusion or bolus injection. CKD-602 treatment caused gastrointestinal symptoms such as diarrhea, soft stool, and soiled perineal region. It also decreased body weight at doses of 9 and 27 mg/kg in a dose-dependant manner. At 3 mg/ kg, clinical signs and body weight decrease were more severe in the infusion group than in the bolus group. In the bolus group, mortalities were 0/8, 0/8, 1/8, and 3/8 at 0, 3, 9, and 27 mg/kg, respectively, whereas those were 0/8, 1/8, 8/8, and 8/8 in the infusion group. $LD_{50}$ values were 36.25 mg/kg for bolus and 3.50 mg/kg for infusion, respectively. This finding indicates that the toxic potency of CKD-602 by continuous infusion is about 10 times higher than by bolus injection. Our findings suggest that the toxic effects of CKD-602 are dependant upon the duration of intravenous administration.

Keywords

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, Wand Grem, J. (1996): Phase I and pharmacokinetic study of 9aminocamptothecin given as a 72-hour infusion in adult cancer patients. J. Clin. Oncol., 14, 1236-1244
  3. Jung, L.L. and Zamboni, WC. (2001): Cellular, pharmacokinetic, and pharmacodynamic aspects of response to camptothecins: can we improve it? Drug Resistance Updates, 4, 273-288
  4. Edelman, E.R. and Karnovsky, M.J. (1994): Contrasting effects of the intermittent and continuous administration of heparin in experimental restenosis. Circulation, 89, 770-776 https://doi.org/10.1161/01.CIR.89.2.770
  5. Evans, J.G. and Kerry, P.J. (2000): Common pathological findings in continuous infusion studies. In: Guy healing and David Smith (eds.) Handbook of preclinical continuous intravenous infusion. Taylor & Francis, pp 253-264
  6. Flynn, J.L., Chan, J., Triebold, KJ., Dalton, O.K., Stewart, T.A. and Bloom, B.R. (1993): An essential role for interferon gamma in resistance to mycobacterium tuberculosis infection. Journal of Experimental Medicine, 178, 2249-2254 https://doi.org/10.1084/jem.178.6.2249
  7. Gargosky, S.E., Tapanainen, P. and Rosenfeld, R.G. (1994): Administration of growth hormone (GH), but not insulinlike growth tactor-t (IGF-I), by continuous infection can induced the formation of the 150-kilodalton IGF-binding protein-3 complex in GH-deficient rats. Endocrinology, 134, 2267-2276 https://doi.org/10.1210/en.134.5.2267
  8. 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). Cancer Chemother. Rep., 54, 461-470
  9. Hertzberg, R.P., Caranta, M.J., Holden, KG., Jakas, D.R., Gallagher, G., Mattern, M.R., Mong, S.M., Bartus, J.D., Johnson, R.K. and KingsbUry, WD. (1989): Modification of the hydroxy lactone ring of camptothecin: Inhibition of mammalian topoisomerase I and biological activity. J. Med. Chern., 32, 715-720
  10. Kim, C.-Y., Imai, Y., Itoi, K, Hashimoto, J., Nobunaga, T., Satoh, H. and Abe, K. (1996): Analysis of circadian variation of blood pressure and heart rate in dexamethasoninduced hypertensive rats. Clin. Exper. Hypertension, 18, 65-76
  11. Kolimannsberger, C., Mross, K, Jakob, A, Kanz, L. and Bokemyer, C. (1999): Topotecan - A novel topoisomerase I inhibitor: Pharmacology and clinical experience. Oncology, 56, 1-12 https://doi.org/10.1159/000011923
  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)- camptothecin, CKD602, as a potent DNA topoisomerase I inhibitor. Arch. Pharm. Res., 21, 581-590.
  13. 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. Cancer Chemother. Rep., 56, 95-101
  14. Pizzolato, J.F. and Saltz, L.B. (2003): The camptothecins.Lancet, 361, 2235-2242
  15. Schaeppi, U., Fleischman, E.w. and Cooney, D.A. (1974): Toxicity of Camptothecin (NSC-100880). Cancer Chemother Rep., 5, 25-3
  16. 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
  17. Takimoto, C.H., Wright, J. and Arbuck, S.G. (1998): Clinical applications of the camptothecins. Biochim. Biophys. Acta, 1400, 107-119
  18. Thompson, J., Stewart, C.F. and Houghton, PJ. (1998): Animal models for studying the action of topoisomerase I targeted drugs. Biochim. Biophys Acta, 1400, 301-319 https://doi.org/10.1016/S0167-4781(98)00143-2
  19. Tomas, F.M., Lemmey, A.B., Read, L.C. and Ballard, F.J. (1996): Superior potency of infused IGF-I analogues which bind poorly to IGF-binding proteins is maintained when administered by injection. J. of Endocrinology, 150, 77-84 https://doi.org/10.1677/joe.0.1500077
  20. Wall, ME, Wani, M.C. and Cook, C.E. (1966): Plant antitumor agents. 1. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J. Am. Chem. Soc., 88, 388-3890