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In Vitro Pharmacodynamics of CKD-602 in HT-29 Cells  

Park, In-Sook (Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Ahn, Mee-Ryung (Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Suh, Soo-Kyung (Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Choi, Hong-Serck (Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Sohn, Soo-Jung (Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Yang, Ji-Sun (Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Yoo, Tae-Moo (Catholic Research Institutes of Medical Science, The Catholic University)
Kuh, Hyo-Jeong (Catholic Research Institutes of Medical Science, The Catholic University)
Publication Information
Archives of Pharmacal Research / v.25, no.5, 2002 , pp. 718-723 More about this Journal
Abstract
CKD-602 (7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin) is a recently-developed synthetic camptothecin analogue and currently under clinical development by Chong Kun Dang Pharm (Seoul, Korea). CKD-602 showed potent topoisomerase inhibitory activity in vitro and broad antitumor activity against various human tumor cells in vitro and in vivo in animal models. This study describes the pharmacodynamics of the immediate and delayed cytotoxicity induced by CKD-602 in a human colorectal adenocarcinoma cell line, HT-29, and its intracellular drug accumulation by HPLC. The present study was designed to address whether the higher activity of CKD-602 with prolonged exposure is due to delayed exhibition of cytotoxicity and/or an accumulation of anti proliferative effect on continuous drug exposure. The drug uptake study was performed to determine whether the delayed cytotoxicity is due to a slow drug accumulation in cells. CKD-602 produced a cytotoxicity that was exhibited immediately after treatment (immediate effect) and after treatment had been terminated (delayed effect). Both the immediate and delayed effects of CKD-602 showed a time dependent decrease in 4IC_{50}$ values. Drug uptake was biphasic and the second equilibrium level was obtained as early as at 24hr, indicating that the cumulative and delayed antitumor effects of CKD-602 were not due to slow drug uptake. On the other hand, CKD-602 treatment was sufficient to induce delayed cytotoxicity after 4hr, however, longer treatment (＞24hr) enhanced its cytotoxicity due to the intracellular accumulation of the drug, which requires 24hr to reach maximum equilibrium concentration. In addition, $C^n$$\times$T=h analysis (n=0.481) indicated that increased exposure times may contribute more to the overall antitumor activity of CKD-602 than drug concentration. Additional studies to determine the details of the intracellular uptake kinetics (e.g., concentration dependency and retention studies) are needed in order to identify the optimal treatment schedules for the successful clinical development of CKD-602.
Keywords
CKD-602; Intracellular uptake; Immediate effect; Delayed effect; Pharmacodynamics;
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1 Jew S.S, Kim M.G, Kim H.J., Rho E.Y., Park H.G, Kim J.K, Han H.J, and Lee H. Synthesis and in vitro cytotoxicity of C(20)(RS)-camptothecin analogues modified at both B (or A) and E ring. Bioorg. Med. Chem. Lett., 8, 1797-1800 (1998)   DOI   ScienceOn
2 Kalns J.E., Millenbaugh, N.J., Wientjes, M.G. and Au, J.L-S. Design and analysis of in vitro antitumor pharmacodynamic studies. Cancer Res., 55, 5315-5322 (1995)   PUBMED
3 Kohn, K.W., and Pommier, Y. Molecular and biological determinants of the cytotoxic actions of camptothecins. Perspective for the development of new topoisomerase I inhibitors. Ann. N. Y. Acad. Sci., 922, 11-26 (2000)   DOI   PUBMED
4 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, 922, 324-325 (2000)   PUBMED
5 Levasseur; L.M., Slocum, H.K., Rustum, Y.M., Greco, W.R, Modeling of the time-dependency of in vitro drug cytotoxicity and resistance. Cancer Res., 58, 5749-5761 (1998)   PUBMED
6 Skipper, H.E, The effects of chemotherapy on the kinetics of leukemic cell. Cancer Res., 25, 1544-1550 (1965)   PUBMED
7 Meibohm, B. and Derendorf, H. Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling. Int. J. Clin. Pharmacol. & Ther., 35, 401-413 (1997)   PUBMED
8 van den Bongard, H.J., Mathot, R.A., Beijnen, J.H., and Schellens, J.H., Pharmacokinetically guided administration of chemotherapeutic agents. Clin. Pharmacokinet., 39, 345-367 (2000)   DOI   ScienceOn
9 Wall, M.E., Wani, M.C., Cook, C.E., and Palmer, K.H. Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor rom Camptotheca acuminata. J. Am. Chem. Soc., 88, 3888-3890 (1966)   DOI
10 Gieschke R, and Steimer J.L. Pharmacometrics: modelling and simulation tools to improve decision making in clinical drug development, Eur. J. Drug Metab. Pharmacokinet., 25, 49-58 (2000)   DOI   PUBMED   ScienceOn
11 Oguma, T., Ohshima, Y. and Nakaoka, M. Sensitive high-performance liquid chromatographic method for the determination of the lactone form and the lactone plus hydroxy-acid forms of the new camptothecin derivative DX-8951 in human plasma using fluorescence detection, J. Chromatogr. B. Biomed. Sci. Appl., 740, 237-245 (2000)   DOI   PUBMED   ScienceOn
12 Jung L.L, and Zamboni W.C. Cellular, pharmacokinetic, and pharmacodynamic aspects of response to camptothecins: can we improve it? Drug Resist. Updat., 4, 273-288 (2001)   DOI   ScienceOn
13 Lee, J.H., Lee, J.M., Kim, J.K., Ahn, S.K., Lee, S.J., Kim, MY., 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., 21, 581-590 (1998)   DOI   ScienceOn
14 Vigano, L., Locatelli, A., Grasselli, G., and Gianni, L., Drug interactions of paclitaxel and docetaxel and their relevance for the design of combination therapy. Invest. New Drugs, 19, 179-196 (2001)   DOI   ScienceOn
15 Kuh, H. J., Jang, S.H., Wientjes, M.G., Weaver, J.R. and Au, J.-S. Determinants of paclitaxel penetration and accumulation in human solid tumor. J. Pharmacol. & Exp. Ther., 871-880, 290 (1999)   PUBMED
16 Li, M.L, Horn, L, Firby, P.S., and Moore, M.J., Pharmacological determinants of 9-aminocamptothecin cytotoxicity. Clin. Cancer Res., 7, 168-174 (2001)   PUBMED
17 Takimoto, C.H., Wright, J, and Arbuck, S.G., Clinical applications of the camptothecins. Biochim. Biaphys. Acta, 1400, 107-119 (1998)   DOI   ScienceOn
18 Slichenmyer, W.J., Rowinsky, E.K., Donehower, R.C., and Kaufmann, S.H., The current status of camptothecin analogues as antitumor agents. J. Natl. Cancer. Inst., 85, 271-291 (1993)   DOI   PUBMED
19 Au, J.L-S., Li, D., Gan, Y, Gao, X., Johnson, A.L., Johston, J., Millenbaugh, N.J., Jang, S.H., Kuh, H.,Chen, C. and Wientjes, M.G., Pharmacodynamics of immediate and delayed effects of paclitaxel: Role of slow apoptosis and intracellular drug retention. Cancer Res., 58, 2141-2148 (1998)   PUBMED
20 Kuh, H. J., Jang, S.H., Wientjes, M.G., Weaver, J.R. and Au, J.-S. Computational model of intracellular pharmacokinetics of paclitaxel, J. Pharmacol. & Exp. Ther., 293, 761-770 (2000)   PUBMED
21 Gerrits, C.J., Schellens, J.H., Burris, H., Eckardt, JR, Planting, A.S., van BeurderBurg, A.M., Rodriguez, G.I. Loos, W.J. van Beurden V. and Verwei, J., A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan. Clin. Cancer Res., 5, 69-75 (1999)   PUBMED
22 Beijnen, ,J.H., Smiti, B.R., Keijer, W.J., Van Gijn, R., Ten Bokkel Huinink, W.W., Vlasveli, L. T., Rodenhuis, S. and Underberg, W, J. M., High-performance liquid chromatographic analysis of the new antitumor drug SK&F 104864-A(NSC 609699) in plasma. J. Pharm. & Biorn. Anal., 8, 789-794 (1990)   DOI   ScienceOn
23 Creemers, G.J., Lund. B. and Verweij, J., Topoisomerase I inhibitors: topotecan and irenotecan. Cancer Treat. Rev., 20, 73-96 (1994)   DOI   ScienceOn