A5077260725- Acute Myeloid Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Drug Transport and Resistance Mechanisms
- Cancer Treatment and Pharmacology
- Colorectal Cancer Treatments and Studies
- Cancer therapeutics and mechanisms
- Pharmacogenetics and Drug Metabolism
- HER2/EGFR in Cancer Research
- PI3K/AKT/mTOR signaling in cancer
- Melanoma and MAPK Pathways
- Acute Lymphoblastic Leukemia research
- Lung Cancer Treatments and Mutations
- Neutropenia and Cancer Infections
- Click Chemistry and Applications
- Hepatocellular Carcinoma Treatment and Prognosis
- Protein Degradation and Inhibitors
- HIV/AIDS drug development and treatment
- Cancer, Hypoxia, and Metabolism
- Histone Deacetylase Inhibitors Research
- Cancer Genomics and Diagnostics
- Multiple Myeloma Research and Treatments
- Metabolism and Genetic Disorders
- Metal complexes synthesis and properties
- Pancreatic and Hepatic Oncology Research
The Ohio State University
2016-2025
Ohio University
1992-2024
Comprehensive Blood & Cancer Center
2024
National Cancer Institute
2000-2023
Azienda Ospedaliera San Gerardo
2023
Istituti di Ricovero e Cura a Carattere Scientifico
2023
Showa University
2023
Meiji Pharmaceutical University
2023
Tottori University
2023
National Institutes of Natural Sciences
2023
Abstract Purpose: To examine the enzyme kinetics of gefitinib and erlotinib metabolism by individual cytochrome P450 (CYP) enzymes, to compare their effects on CYP3A activity, with aim better understand mechanisms underlying pharmacokinetic variability clinical effects. Experimental Design: Enzyme were examined incubating or (1.5-50 μmol/L) recombinant human CYP3A4, CYP3A5, CYP2D6, CYP1A1, CYP1A2, CYP1B1 (10-160 pmol/mL). Their activity comparing midazolam in presence absence liver...
Abstract Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define genomic landscape pAML, we systematically categorized 887 pAML into 23 mutually distinct molecular categories, including new major entities such as UBTF or BCL11B , covering 91.4% cohort. These categories were associated with unique expression profiles and mutational...
The prescribed dose of anticancer agents is most commonly calculated using body surface area as the only independent variable, and it has been shown that this approach still results in large interpatient variability drug exposure. Here, we retrospectively assessed pharmacokinetics 33 investigational tested phase I trials from 1991 through 2001, a function 1650 adult cancer patients. Twelve drugs were administered orally, 19 intravenously, two by both routes. Body area-based dosing was...
Abstract This study tested the hypothesis that number of CA single sequence repeat (CA-SSR) in intron 1 epidermal growth factor receptor (egfr) gene, which affects transcription efficiency is associated with response to EGFR inhibitors. To this end, we determined dinucleotides egfr gene a panel 12 head and neck cancer cell lines lack amplification measured expression (mRNA protein), as well inhibition. Cells lower CA-SSR had higher protein were more sensitive inhibitory effects erlotinib,...
Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase with activity in non–small-cell lung cancer. Diarrhea and skin toxicity are prominent gefitinib-related adverse events that potentially limit its use. a substrate for ABCG2 (ABCP, BCRP, MXR), polymorphic efflux transporter protein highly expressed intestines liver. Here we investigated associations between allelic variants EGFR, ABCG2, ABCB1 diarrhea gefitinib-treated patients. One variant, common...
Abstract Purpose: The activity of imatinib in leukemia has recently been linked with expression the organic cation transporter 1 (OCT1) gene SLC22A1. Here, we characterized contribution solute carriers to transport an effort further understand mechanisms involved intracellular uptake and retention (IUR) drug. Experimental Design: IUR [3H]imatinib was studied Xenopus laevis oocytes HEK293 cells expressing OATP1A2, OATP1B1, OATP1B3, OCT1-3, OCTN1-2, or OAT1-3. Gene determined nine cell lines...
The purpose of the study was to determine if epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, are substrates for efflux transporter ABCG2, investigate relevance ABCG2 421C>A (Q141K) polymorphism pharmacokinetics gefitinib. Gefitinib erlotinib transport in vitro studied using HEK293 cells transfected with wild-type or a Q141K clone. determined 27 cancer patients. was. ABCB1 3435C>T genotypes were direct sequencing. Cells expressing exhibited...
The purpose of this study was to evaluate the affinity docetaxel for 14 transporter proteins and assess functional significance 17 variants in five genes involved drug elimination. Among transfected models investigated, OATP1B3 (SLCO1B3) identified as most efficient influx docetaxel. None observed genotypes (SLCO1B3, ABCB1, ABCC2) related with clearance 92 white patients (P > 0.17). However, simultaneous presence CYP3A4*1B CYP3A5*1A alleles associated a 64% increase = 0.0015), independent...
Purpose Despite the rising prevalence of obesity, there is paucity information describing how doses anticancer drugs should be adjusted in clinical practice. Here, we assessed pharmacokinetics eight adults and evaluated potential utility alternative weight descriptors dose calculation for obese. Patients Methods A total 1,206 adult cancer patients were studied, whom 162 (13.4%) obese (body mass index ≥ 30). Pharmacokinetic parameters calculated using noncompartmental analysis, compared...
Abstract Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human solute carriers SLC22A SLCO families, transport inhibition efflux ATP-binding cassette (ABC) transporters, role ABCB1 plasma pharmacokinetics brain penetration these agents. Experimental Design: Uptake [3H]sorafenib or [3H]sunitinib was assessed Xenopus laevis oocytes mammalian cells transfected with cDNAs coding for OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, OCTN2. Efflux experiments...
To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine cytarabine children relapsed/refractory leukemia.Twelve patients acute leukemia (11 myeloid [AML]) received on days 1 to 7 then concurrently (1 g/m(2)) (stratum one: 40 mg/m(2), n = 10; stratum two [recent transplantation or fungal infection]: 20 2) 8 12. Sorafenib was continued until day 28 if tolerated. Two dose levels (200 mg/m(2) 150 twice daily) were planned....
Abstract Purpose: Many tyrosine kinase inhibitors (TKI) undergo extensive hepatic metabolism, but mechanisms of their hepatocellular uptake remain poorly understood. We hypothesized that liver TKIs is mediated by the solute carriers OATP1B1 and OATP1B3. Experimental Design: Transport crizotinib, dasatinib, gefitinib, imatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, vemurafenib was studied in vitro using artificial membranes (PAMPA) HEK293 cell lines stably transfected with...
FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit heavily pretreated relapsed/refractory patients, responses transient relapse eventually occurs. Here, to investigate the mechanisms of resistance, we perform whole exome sequencing patient samples...
Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well toxicities. Here we report a unique phosphorylation-dependent interaction between tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation transporters. We initially found that organic cation (OCTs), uptake carriers metformin oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies...
In 2018, a patient received capecitabine without prior testing for dihydropyrimidine dehydrogenase (DPYD) and later presented with vomiting, rash, diarrhea.The hospital failed to provide uridine triacetate in timely fashion, the died.The patient's widow filed wrongful death lawsuit against Oregon Health Sciences University (OHSU) assisted formation of nonprofit organization advocate DPYD fluoropyrimidines.A settlement $1 million US dollars was reached requiring OHSU oncologists undergo...