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Kenneth K Chan PhD

Kenneth K Chan PhD
ProfessorCollege of Pharmacychan.56@osu.edu
302 OSUCCC 410 W 12th Avenue Columbus OH 43210
Phone:614-292-8294Fax: 614-292-7766
  • Non-Member

General Research Interest

Pharmacokinetics, metabolite and clinical pharmacokinetics; clinical studies; cancer drug development, drug metabolism, drug analytical method development, stable isotope labeling, liquid-chromatographic mass spectrometry, application of stable isotopes in pharmacokinetic and drug metabolism research, cancer chemotherapy and modulation, and antisense drug therapy.

Research Description

Kenneth Chan's laboratory is known for work in preclinical and clinical pharmacology research and novel analytical method development for antitumor agents. His research interests include preclinical and early clinical anticancer drug development, preclinical pharmacology of anticancer drugs, pharmacokinetics, metabolite pharmacokinetics, preclinical and clinical pharmacokinetics, drug metabolism, novel drug analytical method development, mass spectrometry and liquid chromatography-mass spectrometry, application of stable isotopes in pharmacokinetic and drug metabolism research, cancer chemotherapy and modulation, drug combination and antisense drug therapy development. The Chan laboratory collaborates with many Ohio State investigators including; John Byrd, MD; Michael Caliguiri, MD; Ching-Shih Chen, PhD; Carlo Croce, MD; Michael Grever, MD; Guido Marcucci, MD, Gary Stoner, PhD; Susan Mallery, DDS; Manisha Shah, MD; Miguel Villalona, MD—among others.

Transinstitutional Work

In conjunction with the NCI Contract N01-CM-52205, work assignment No. 9 entitled “LC-MS/MS Analysis of Global DNA Methylation in Human Tumors after In Vitro and In Vivo Treatments with 5-fluoro-2'-deoxycytidine (FdC; NSC 48006) +/- THU (NSC 112907)” we collaborated with Dr. James Doroshow at the National Cancer Institute [(Laboratory of Human Toxicology & Pharmacology (LHTP), DTP, DCTD, NCI)], and Dr. Edward Newman, City of Hope National Cancer Center, on the evaluation of the global DNA methylation effect assessment of the 5-fluoro-2'-deoxycytidine (FdC; NSC 48006) in the absence and presence of tetrahydrouridine. We utilized our previously developed Global DNA Methylation method [Liu et al., Nuc. Acid Res. 35(5) 2007], which is also a method now widely used in the PhASR to evaluate the aforementioned drug/drug combination in a human tumor xenografted mouse model. Additionally, we will determine the DNA incorporation of FdC and other macromolcules in tumor or surrogate tissues. We have found that a significant global DNA hypomethylation activity of 5-FdC was observed in MDA-MB-231T and MCF-7 cells exposed to moderate to high concentration of FdC. However, the hypomethylation activity of 5-FdC is rather short-lived and THU might compromise its hypomethylation effect. There was evidence for the hypomethylation of tissue samples, which is subject to a number of variables. Additionally, we modified and validated an LC-MS/MS method for the quantification of decitabine, a method used for PhASR to support clinical trials, in mouse plasma with a lower limit of quantitation of 2 ng/mL and provided plasma pharmacokinetics for human cancer cell engrafted nude mice. Finally, an LC-MS/MS method for study of the incorporation of 5-FdC and its deaminated product 5-FdU and global DNA methylation was developed and we have found DNA incorporation of FdC. A meeting abstract was presented (Liu, et al., Proc. AACR, April 2009, Denver, CO. We have continued a long-term collaboration with Dr. Mimi C. Yu (University of Minnesota), and Dr. Ronald K. Ross (University of Southern California Norris Comprehensive Cancer Center) on projects relating to exposure to carcinogens, cigarette smoking, genetic determinants, and bladder cancer risk, which resulted in a number of publications in high impact journals [Yuan et al., Carcinogenesis, 29(7), 1386 (2008); Stram et al., Nutrition and Cancer, 57(2): 123-129, 2006; Castelao et al., Int J Cancer 110: 417-423, 2004; Gago-Dominguez et al., Carcinogenesis. 24(3):483-489, 2003]. In those studies, we provided the nicotine/cotinine measurements and the N-acetylation phenotyping (NAT1 and NAT2) on human subjects and found strong a correlation between slow acetylators with higher levels of 4-amino-biphenyl hemoglobin adducts, which is one of the indicators for cigarette smoke related bladder cancer. Recently, through the NIH RAID project for Dr. Yogen Saunthararajah, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic Foundation, we have established a significant collaboration in a project entitled “Malignant stem-cell specific differentiation therapy.” This has resulted a recently funded grant from the US Department of Defense and a portion of the project is subcontracted to our laboratory. Our function is to investigate the pharmacokinetic of decitabine in a transgenic mouse model for human cytokine production (SGM3/NOG) singly and in a new formulation combing with tetrahydrouridine (THU) and in a nano novel pre-activated formulation, all at non-DNA damaging doses. We will also measure the intracellular decitabine triphosphate levels in cell lines and other relevant tissues. The data and intracellular are to be correlated with the DMNT1 depletion and other relevant biomarkers. It is believed that these approaches will have clinical potential to selectively differentiate stem cells, while increasing the self-renewal of normal stem cells. Another related project is to optimize non-DNA damaging DNMT1 depletion therapy for cancer.

Current Publications

  • Huang X, Schwind S, Yu B, Santhanam R, Wang H, Hoellerbauer P, Mims A, Klisovic RB, Walker A, Chan KK, Blum W, Perrotti D, Byrd JC, Bloomfield CD, Caligiuri MA, Lee RJ, Garzon R, Muthusamy N, Lee LJ, Marcucci GTargeted Delivery of microRNA-29b by Transferrin-Conjugated Anionic Lipopolyplex Nanoparticles: A Novel Therapeutic Strategy in Acute Myeloid Leukemia.Clin Cancer Res 19(9) 2355-67 5/1/2013
  • Mims A, Walker AR, Huang X, Sun J, Wang H, Santhanam R, Dorrance AM, Walker C, Hoellerbauer P, Tarighat SS, Chan KK, Klisovic RB, Perrotti D, Caligiuri MA, Byrd JC, Chen CS, Lee LJ, Jacob S, Mrózek K, Bloomfield CD, Blum W, Garzon R, Schwind S, Marcucci GIncreased anti-leukemic activity of decitabine via AR-42-induced upregulation of miR-29b: a novel epigenetic-targeting approach in acute myeloid leukemia.Leukemia 27(4) 871-8 4/1/2013
  • Yu B, Mao Y, Bai LY, Herman SE, Wang X, Ramanunni A, Jin Y, Mo X, Cheney C, Chan KK, Jarjoura D, Marcucci G, Lee RJ, Byrd JC, Lee LJ, Muthusamy NTargeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia.Blood 121(1) 136-47 1/3/2013
  • Yu J, Peng Y, Wu LC, Xie Z, Deng Y, Hughes T, He S, Mo X, Chiu M, Wang QE, He X, Liu S, Grever MR, Chan KK, Liu ZCurcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia.PLoS One 8(2) e55934 1/1/2013
  • Chu BF, Karpenko MJ, Liu Z, Aimiuwu J, Villalona-Calero MA, Chan KK, Grever MR, Otterson GAPhase I study of 5-aza-2'-deoxycytidine in combination with valproic acid in non-small-cell lung cancer.Cancer Chemother Pharmacol 71(1) 115-21 1/1/2013
  • Wang H, Chen P, Wang J, Santhanam R, Aimiuwu J, Saradhi UV, Liu Z, Schwind S, Mims A, Byrd JC, Grever MR, Villalona-Calero MA, Klisovic R, Walker A, Garzon R, Blum W, Chan KK, Marcucci GIn vivo quantification of active decitabine-triphosphate metabolite: a novel pharmacoanalytical endpoint for optimization of hypomethylating therapy in acute myeloid leukemia.AAPS J 15(1) 242-9 1/1/2013
  • Alachkar H, Xie Z, Marcucci G, Chan KKDetermination of cellular uptake and intracellular levels of Cenersen (Aezea(®), EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells.J Pharm Biomed Anal 71 228-32 12/1/2012
  • Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, Schaefer D, Falkenberg LG, Sullivan L, Jaroncyk L, Yang X, Fisk H, Wu LC, Hickey C, Chandler JC, Wu YZ, Heerema NA, Chan KK, Perrotti D, Zhang J, Porcu P, Racke FK, Garzon R, Lee RJ, Marcucci G, Caligiuri MAAberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation.Cancer Cell 22(5) 645-55 11/13/2012
  • Chen W, Fan-Havard P, Yee LD, Cao Y, Stoner GD, Chan KK, Liu ZA liquid chromatography-tandem mass spectrometric method for quantification of curcumin-O-glucuronide and curcumin in human plasma.J Chromatogr B Analyt Technol Biomed Life Sci 900 89-93 7/1/2012
  • Blum W, Schwind S, Tarighat SS, Geyer S, Eisfeld AK, Whitman S, Walker A, Klisovic R, Byrd JC, Santhanam R, Wang H, Curfman JP, Devine SM, Jacob S, Garr C, Kefauver C, Perrotti D, Chan KK, Bloomfield CD, Caligiuri MA, Grever MR, Garzon R, Marcucci GClinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.Blood 119(25) 6025-31 6/21/2012
  • Wang H, Chiu M, Xie Z, Chiu M, Liu Z, Chen P, Liu S, Byrd JC, Muthusamy N, Garzon R, Croce CM, Marcucci G, Chan KKSynthetic microRNA cassette dosing: pharmacokinetics, tissue distribution and bioactivity.Mol Pharm 9(6) 1638-44 6/4/2012
  • Aimiuwu J, Wang H, Chen P, Xie Z, Wang J, Liu S, Klisovic R, Mims A, Blum W, Marcucci G, Chan KKRNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia.Blood 119(22) 5229-38 5/31/2012
  • Tao L, Xiang YB, Chan KK, Wang R, Gao YT, Yu MC, Yuan JMCytochrome P4501A2 phenotype and bladder cancer risk: The Shanghai bladder cancer study.Int J Cancer 130(5) 1174-83 3/1/2012
  • Zhongfa L, Chiu M, Wang J, Chen W, Yen W, Fan-Havard P, Yee LD, Chan KKEnhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice.Cancer Chemother Pharmacol 69(3) 679-89 3/1/2012
  • Gupta SV, Sass EJ, Davis ME, Edwards RB, Lozanski G, Heerema NA, Lehman A, Zhang X, Jarjoura D, Byrd JC, Pan L, Chan KK, Kinghorn AD, Phelps MA, Grever MR, Lucas DMResistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells.AAPS J 13(3) 357-64 9/1/2011
  • Saradhi UV, Gupta SV, Chiu M, Wang J, Ling Y, Liu Z, Newman DJ, Covey JM, Kinghorn A, Marcucci G, Lucas DM, Grever MR, Phelps A, Chan KKCharacterization of silvestrol pharmacokinetics in mice using liquid chromatography-tandem mass spectrometry.AAPS J 13(3) 347-56 9/1/2011
  • Hofmeister CC, Yang X, Pichiorri F, Chen P, Rozewski DM, Johnson AJ, Lee S, Liu Z, Garr CL, Hade EM, Ji J, Schaaf LJ, Benson DM Jr, Kraut EH, Hicks WJ, Chan KK, Chen CS, Farag SS, Grever MR, Byrd JC, Phelps MAPhase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein.J Clin Oncol 29(25) 3427-34 9/1/2011
  • Mallery SR, Budendorf DE, Larsen MP, Pei P, Tong M, Holpuch AS, Larsen PE, Stoner GD, Fields HW, Chan KK, Ling Y, Liu ZEffects of human oral mucosal tissue, saliva, and oral microflora on intraoral metabolism and bioactivation of black raspberry anthocyanins.Cancer Prev Res (Phila) 4(8) 1209-21 8/1/2011
  • Wang H, Zhang C, Rorick A, Wu D, Chiu M, Thomas-Ahner J, Chen Z, Chen H, Clinton SK, Chan KK, Wang QCCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability.Cancer Res 71(14) 4866-76 7/15/2011