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Novel Antimitotic Compounds with Potent In Vitro and In Vivo Antitumor Effects: the Use of Pharmacokinetics, Metabolism, Efficacy, and Toxicity Studies

Ahn, Sunjoo
http://rave.ohiolink.edu/etdc/view?acc_num=osu1281966697

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Pharmacy.
We identified novel indole derivatives inhibiting human cancer cell growth with nanomolar IC50 values. Thus, we studied the mechanism of anticancer effects, pharmacokinetics, in vitro hepatic metabolism, in vivo efficacy, and/or toxicity of lead compounds I-13 and I-19. They induced a down-regulation and/or an inactivation by hyper-phosphorylation of Bcl-2. They arrested cells in the G2M phase and inhibited tubulin polymerization by binding to the colchicine-binding site. The pharmacokinetics of the lead compound, I-19, in ICR mice was determined after i.v., i.p., and p.o. administrations. I-19 was slowly cleared and highly distributed in mice. I.p. administration of I-19 was absorbed quickly with 65-94% bioavailability. In the in vitro metabolic stability study using mouse, rat, dog, monkey, and human liver microsomes, I-19 was metabolized mainly via phase I pathway and the metabolite with a reduced ketone was the predominant form by human liver microsomes. In the PC-3 xenograft models, I-13 (10 mg/kg, q2d, i.p.) and I-19 (10 mg/kg, q2w, i.p.) inhibited 58% and 68% tumor growth, respectively. Furthermore, since multidrug resistant (MDR) cell lines that over-expressed ATP-binding cassette (ABC) transporters such as P-glycoprotein were not resistant to indole compounds, in vivo efficacy of I-19 was examined in xenografts using MES-SA/DX5 cells over-expressing P-glycoprotein. I-19 (10 mg/kg, q2d, i.p.) was effective with 76% tumor growth inhibition in xenograft models using MES-SA or MES-SA/DX5 cells. In vitro studies of NGF-dependent neurite outgrowth in PC12 cells and in vivo studies of mouse behavior showed that I-19 was less neurotoxic than vinblastine and vincristine, tubulin destabilizers with known neurotoxicity. In conclusion, indole compounds inhibit tubulin polymerization via the colchicine binding site and circumvent P-glycoprotein-mediated MDR, suggesting that they may be new antimitotic agents for the treatment of patients with drug resistant cancer.
James Dalton, PhD (Advisor)
Robert Brueggemeier, PhD (Committee Member)
Thomas Schmittgen, PhD (Committee Member)
Mitch Phelps, PhD (Committee Member)
Pharmaceuticals
drug; discovery; tubulin; indole; P-glycoprotein; prostate cancer

Recommended Citations

Citations

  • Ahn, S. (2010). Novel Antimitotic Compounds with Potent In Vitro and In Vivo Antitumor Effects: the Use of Pharmacokinetics, Metabolism, Efficacy, and Toxicity Studies [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1281966697

    APA Style (7th edition)

  • Ahn, Sunjoo. Novel Antimitotic Compounds with Potent In Vitro and In Vivo Antitumor Effects: the Use of Pharmacokinetics, Metabolism, Efficacy, and Toxicity Studies. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1281966697.

    MLA Style (8th edition)

  • Ahn, Sunjoo. "Novel Antimitotic Compounds with Potent In Vitro and In Vivo Antitumor Effects: the Use of Pharmacokinetics, Metabolism, Efficacy, and Toxicity Studies." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1281966697

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.