A5022029681- Acute Myeloid Leukemia Research
- Advanced Breast Cancer Therapies
- Histone Deacetylase Inhibitors Research
- Acute Lymphoblastic Leukemia research
- HIV/AIDS drug development and treatment
- Chronic Lymphocytic Leukemia Research
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Folate and B Vitamins Research
- Protein Degradation and Inhibitors
- Lung Cancer Research Studies
- Cancer Treatment and Pharmacology
- PARP inhibition in cancer therapy
- HER2/EGFR in Cancer Research
- Multiple Myeloma Research and Treatments
- Pneumocystis jirovecii pneumonia detection and treatment
- Chronic Myeloid Leukemia Treatments
- Metabolism and Genetic Disorders
- Colorectal Cancer Treatments and Studies
- Pancreatic and Hepatic Oncology Research
- Drug Transport and Resistance Mechanisms
- Biochemical and Molecular Research
- Neuroendocrine Tumor Research Advances
- Viral-associated cancers and disorders
- Myeloproliferative Neoplasms: Diagnosis and Treatment
Epigenetix (United States)
2023
Cyclacel Pharmaceuticals (United Kingdom)
2007-2021
Cyclacel Pharmaceuticals (United States)
2009-2019
The University of Texas MD Anderson Cancer Center
2009
National University Hospital
2009
Princess Margaret Cancer Centre
2009
Merck (Japan)
2008
Merck & Co., Inc., Rahway, NJ, USA (United States)
2006-2007
Gwynedd Mercy University
2007
Cornell University
2005
Purpose To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. Patients Methods solid hematologic malignancies were treated oral SAHA once or twice a day on continuous basis daily for 3 consecutive days per week. Pharmacokinetic profile bioavailibity determined. Western blots enzyme-linked immunosorbent assays histones isolated from...
To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks.Twenty-seven patients with a median age 58 years received 85 cycles using an intrapatient interpatient dose escalation schema. Drug was at escalating doses as solution (25 to 850 mg bid) or pellet capsules (500 1300 bid). Pharmacokinetics were assessed after first last during cycle 1.Dose-limiting toxicity...
A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle 300, 400 14 days/3-week until progressive disease intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives to determine maximum tolerated doses (MTDs) and assess activity safety. Thirteen patients (median age, 63 years; median prior therapies, 3) enrolled. MTDs not determined due early study termination by sponsor...
Abstract Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects seliciclib, cyclin-dependent kinase (CDK) inhibitor, were studied patients with Experimental Design: Patients treatment-naïve locally advanced carcinoma received seliciclib at 800 mg or 400 twice daily on days 1 to 3 8 12. Paired tumor samples obtained baseline day 13 assessed by light...
Mediated folate compound transport inward in isolated luminal epithelial cells from mouse small intestine was delineated as pH-dependent and non-pH-dependent components on the basis of their differential sensitivity to stilbene inhibitor, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid. pH dependence manifested higher maximum capacity (Vmax) for influx l,L-5-CH3-H4folate at acidic compared with neutral or alkaline no effect saturability (Km). The component relatively insensitive...
Histone deacetylase (HDAC) inhibitors represent a new class of targeted anticancer agents. A number structural classes HDAC have been developed which several are in clinical trials, including phenylbutyrate (PB) and related compounds; the hydroxamic acids, suberoylanilide acid (SAHA) depsipeptide (FK-228); benzamides, MS-275 C1-994. This review will focus on our studies with inhibitors, SAHA is lead agent. X-ray crystallographic homologue (HDLP) demonstrated that group, most aliphatic chain...
Sapacitabine is an oral deoxycytidine nucleoside analog with a unique mechanism of action that different from cytarabine.To define the dose-limiting toxicities (DLT) and maximum-tolerated dose (MTD) sapacitabine given orally twice daily for 7 days every 3 to 4 weeks, or 2 weeks (days 1 through 8 10) in refractory-relapse acute leukemia myelodysplastic syndrome (MDS). A total 47 patients were treated phase I study used classical + design. was escalated 75 375 mg (n = 35) 475 on 10.The DLTs...
The apparent Km, but notVmax, for influx of methotrexate (MTX) mediated through the plasma membrane S180 cells by one-carbon, reduced folate transporter as well KD binding to were 4-fold higher than in L1210 correlating with greater intrinsic resistance former this analogue. In contrast, no difference was observed between each cell type regard efflux [3H]MTX same ATP-depleted cells. influxKm case 10-methyl substituted N1O analogue folic acid not seen more effective permeants, such...
This study assessed the antiproliferative activity of sapacitabine (CYC682, CS-682) in a panel 10 human cancer cell lines with varying degrees resistance or sensitivity to commonly used nucleoside analogues ara-C and gemcitabine. Growth inhibition studies using CNDAC were performed compared both other anticancer compounds including oxaliplatin, doxorubicin, docetaxel seliciclib. Sapacitabine displayed across range concentrations variety lines, those shown be resistant several drugs. is...
6026 Background: Seliciclib is a selective inhibitor of cyclin dependent kinases (CDKs) 2, 7 and 9. In phase I study 2 weeks oral administration, clinical antitumor activity was observed in patients with treatment-naive nasopharyngeal carcinoma (NPC) biological effects consistent CDK inhibition were detected tumor biopsy samples. We are conducting multicenter, randomized to evaluate the safety efficacy prolonged administration seliciclib previously treated NPC. The has lead-in where...
Folate compound transport into Fisher rat 3T3 (FR3T3) cells at physiological pH occurs predominantly by an acid pH-dependent, mobile carrier system. However, influx of [3H]MTX this system is 3–4-fold higher 6 than 7.5, the optimum for RFC-1–mediated folate transport. This dependency reflects alteration Vmax rather Km in these different pH. Acid pH-dependent interacts effectively with MTX, 5ℓLCHO-folateH4, 5ℓLCH3-folateH4 and folic as permeants (influx Ki = 2.7–5.3 μM). The relative...
2503 Background: Sapacitabine is an oral nucleoside analogue; the active metabolite CNDAC generates ssDNA breaks that are converted to dsDNA (DSB) during subsequent replication, resulting in cell death. CNDAC-induced DSB repair dependent on homologous recombination (HR). Seliciclib CDK2, 7 and 9 inhibitor, sensitizes cells by decreasing via compromise of HR protein activation. This phase I study evaluates sequential concomitant sapacitabine seliciclib treatment. Methods: Dose escalation was...
Abstract Background: CYC065 is a potent and selective inhibitor of CDK2 CDK9. drives cell cycle transition activates major DNA double-strand break repair pathways; CDK9 regulates transcription genes through phosphorylation RNAP II. This first-in-human phase 1 study evaluates administered by 4-hour infusion every 3 weeks in patients with advanced cancers. Methods: Dose escalation was 100% initially. Upon the occurrence first grade 2 drug-related toxicity, dose decreased to 50% then 25% upon...
5578 Background: SAHA is a potent histone deacetylase inhibitor that has excellent oral bioavailability. Preclinical studies demonstrated growth inhibitory and apoptosis-inducing activity in SCCHN cell lines vitro. In phase I trial of administered once day or twice day, partial response was observed pt with metastatic laryngeal carcinoma. A II initiated to assess the efficacy safety as 400 mg qd pts SCCHN. Methods: Eligible must have recurrent and/or unresponsive intolerant conventional...