General Research InterestPharmacokinetics, 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 DescriptionKenneth 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 WorkIn 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.