Publications by authors named "Kenneth K Chan"

104 Publications

Chest ultrasonography versus supine chest radiography for diagnosis of pneumothorax in trauma patients in the emergency department.

Cochrane Database Syst Rev 2020 07 23;7:CD013031. Epub 2020 Jul 23.

Department of Emergency Medicine, Beaumont Hospital, Dublin, Ireland.

Background: Chest X-ray (CXR) is a longstanding method for the diagnosis of pneumothorax but chest ultrasonography (CUS) may be a safer, more rapid, and more accurate modality in trauma patients at the bedside that does not expose the patient to ionizing radiation. This may lead to improved and expedited management of traumatic pneumothorax and improved patient safety and clinical outcomes.

Objectives: To compare the diagnostic accuracy of chest ultrasonography (CUS) by frontline non-radiologist physicians versus chest X-ray (CXR) for diagnosis of pneumothorax in trauma patients in the emergency department (ED). To investigate the effects of potential sources of heterogeneity such as type of CUS operator (frontline non-radiologist physicians), type of trauma (blunt vs penetrating), and type of US probe on test accuracy.

Search Methods: We conducted a comprehensive search of the following electronic databases from database inception to 10 April 2020: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, Database of Abstracts of Reviews of Effects, Web of Science Core Collection and Clinicaltrials.gov. We handsearched reference lists of included articles and reviews retrieved via electronic searching; and we carried out forward citation searching of relevant articles in Google Scholar and looked at the "Related articles" on PubMed.

Selection Criteria: We included prospective, paired comparative accuracy studies comparing CUS performed by frontline non-radiologist physicians to supine CXR in trauma patients in the emergency department (ED) suspected of having pneumothorax, and with computed tomography (CT) of the chest or tube thoracostomy as the reference standard.

Data Collection And Analysis: Two review authors independently extracted data from each included study using a data extraction form. We included studies using patients as the unit of analysis in the main analysis and we included those using lung fields in the secondary analysis. We performed meta-analyses by using a bivariate model to estimate and compare summary sensitivities and specificities.

Main Results: We included 13 studies of which nine (410 traumatic pneumothorax patients out of 1271 patients) used patients as the unit of analysis; we thus included them in the primary analysis. The remaining four studies used lung field as the unit of analysis and we included them in the secondary analysis. We judged all studies to be at high or unclear risk of bias in one or more domains, with most studies (11/13, 85%) being judged at high or unclear risk of bias in the patient selection domain. There was substantial heterogeneity in the sensitivity of supine CXR amongst the included studies. In the primary analysis, the summary sensitivity and specificity of CUS were 0.91 (95% confidence interval (CI) 0.85 to 0.94) and 0.99 (95% CI 0.97 to 1.00); and the summary sensitivity and specificity of supine CXR were 0.47 (95% CI 0.31 to 0.63) and 1.00 (95% CI 0.97 to 1.00). There was a significant difference in the sensitivity of CUS compared to CXR with an absolute difference in sensitivity of 0.44 (95% CI 0.27 to 0.61; P < 0.001). In contrast, CUS and CXR had similar specificities: comparing CUS to CXR, the absolute difference in specificity was -0.007 (95% CI -0.018 to 0.005, P = 0.35). The findings imply that in a hypothetical cohort of 100 patients if 30 patients have traumatic pneumothorax (i.e. prevalence of 30%), CUS would miss 3 (95% CI 2 to 4) cases (false negatives) and overdiagnose 1 (95% CI 0 to 2) of those without pneumothorax (false positives); while CXR would miss 16 (95% CI 11 to 21) cases with 0 (95% CI 0 to 2) overdiagnosis of those who do not have pneumothorax.

Authors' Conclusions: The diagnostic accuracy of CUS performed by frontline non-radiologist physicians for the diagnosis of pneumothorax in ED trauma patients is superior to supine CXR, independent of the type of trauma, type of CUS operator, or type of CUS probe used. These findings suggest that CUS for the diagnosis of traumatic pneumothorax should be incorporated into trauma protocols and algorithms in future medical training programmes; and that CUS may beneficially change routine management of trauma.
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http://dx.doi.org/10.1002/14651858.CD013031.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390330PMC
July 2020

Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells.

Biomol Ther (Seoul) 2018 Nov;26(6):591-598

Department of Biomedicine & Health Science, Graduate School, The Catholic University of Korea, Seoul 06591, Republic of Korea.

Epigenetic silencing is considered to be a major mechanism for loss of activity in tumor suppressors. Reversal of epigenetic silencing by using inhibitors of DNA methyltransferase (DNMT) or histone deacetylases (HDACs) such as 5-Aza-CdR and FK228 has shown to enhance cytotoxic activities of several anticancer agents. This study aims to assess the combinatorial effects of gene-silencing reversal agents (5-Aza-CdR and FK228) and oxaliplatin in gastric cancer cells, i.e., Epstein-Barr virus (EBV)-negative SNU-638 and EBV-positive SNU-719 cells. The doublet combinatorial treatment of 5-Aza-CdR and FK228 exhibited synergistic effects in both cell lines, and this was further corroborated by Zta expression induction in SNU-719 cells. Three drug combinations as 5-Aza-CdR/FK228 followed by oxaliplatin, however, resulted in antagonistic effects in both cell lines. Simultaneous treatment with FK228 and oxaliplatin induced synergistic and additive effects in SNU-638 and SNU-719 cells, respectively. Three drug combinations as 5-Aza-CdR prior to FK228/oxaliplatin, however, again resulted in antagonistic effects in both cell lines. This work demonstrated that efficacy of doublet synergistic combination using DNMT or HDACs inhibitors can be compromised by adding the third drug in pre- or post-treatment approach in gastric cancer cells. This implies that the development of clinical trial protocols for triplet combinations using gene-silencing reversal agents should be carefully evaluated in light of their potential antagonistic effects.
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http://dx.doi.org/10.4062/biomolther.2018.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254647PMC
November 2018

Aspiration Thrombectomy versus Conventional Catheter-Directed Thrombolysis as First-Line Treatment for Noniatrogenic Acute Lower Limb Ischemia.

J Vasc Interv Radiol 2018 05 22;29(5):607-613. Epub 2018 Mar 22.

Department of Vascular and Endovascular Surgery, Sir Charles Gairdner Hospital, Perth, Western Australia 6009, Australia; School of Public Health, Curtin University, Perth, Western Australia, Australia; Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia; Heart Research Institute, Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.

Purpose: To examine the efficacy, safety, and procedural costs of percutaneous aspiration thrombectomy (PAT) as a first-line treatment for noniatrogenic acute lower limb ischemia (ALI) compared with conventional catheter-directed thrombolysis (CDT).

Materials And Methods: All patients who underwent endovascular intervention for ALI from January 2015 to August 2017 were included. Fifteen patients were treated with the use of primary PAT and 27 patients were treated with the use of primary CDT. The primary end point was complete thrombus clearance with improvement in Thrombolysis in Myocardial Infarction (TIMI) score. Adjunctive treatment for thrombus removal was considered to indicate technical failure. Treatment of underlying chronic disease was not considered to indicate technical failure. Procedural costs for each patient were calculated by itemizing all disposable equipment, facility overheads, and staff costs.

Results: Of the 15 primary PAT patients, technical success was achieved in 8 (53%); the remaining 7 (47%) required adjunctive CDT. Of the 27 primary CDT patients, technical success was achieved in 25 (89%); the remaining 2 (11%) required adjunctive PAT. There were 4 complications in the primary PAT group: 2 were procedure related and of a minor grade. There were 8 complications in the primary CDT group: All were procedure-related, including 2 major groin/retroperitoneal hemorrhage and 1 death from intracranial hemorrhage. Limb salvage was attained in all patients. There were no significant differences in average procedural costs per patient between the 2 groups.

Conclusions: First-line use of PAT for endovascular treatment of ALI can reduce the need for CDT, with no significant cost difference.
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http://dx.doi.org/10.1016/j.jvir.2017.11.030DOI Listing
May 2018

Differential association for N-acetyltransferase 2 genotype and phenotype with bladder cancer risk in Chinese population.

Oncotarget 2016 Jun;7(26):40012-40024

University of Pittsburgh Cancer Institute, and Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: N-acetyltransferase 2 (NAT2) is involved in both carcinogen detoxification through hepatic N-acetylation and carcinogen activation through local O-acetylation. NAT2 slow acetylation status is significantly associated with increased bladder cancer risk among European populations, but its association in Asian populations is inconclusive.

Methods: NAT2 acetylation status was determined by both single nucleotide polymorphisms (SNPs) and caffeine metabolic ratio (CMR), in a population-based study of 494 bladder cancer patients and 507 control subjects in Shanghai, China.

Results: The CMR, a functional measure of hepatic N-acetylation, was significantly reduced in a dose-dependent manner among both cases and controls possessing the SNP-inferred NAT2 slow acetylation status (all P-values<5.0×10-10). The CMR-determined slow N-acetylation status (CMR<0.34) was significantly associated with a 50% increased risk of bladder cancer (odds ratio = 1.50, 95% confidence interval = 1.10-2.06) whereas the SNP-inferred slow acetylation statuses were significantly associated with an approximately 50% decreased risk of bladder cancer. The genotype-disease association was strengthened after the adjustment for CMR and was primarily observed among never smokers.

Conclusions: The apparent differential associations for phenotypic and genetic measures of acetylation statuses with bladder cancer risk may reflect dual functions of NAT2 in bladder carcinogenesis because the former only measures the capacity of carcinogen detoxification pathway while the latter represents both carcinogen activation and detoxification pathways. Future studies are warranted to ascertain the specific role of N- and O-acetylation in bladder carcinogenesis, particularly in populations exposed to different types of bladder carcinogens.
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http://dx.doi.org/10.18632/oncotarget.9475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129988PMC
June 2016

Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

AAPS J 2016 05 4;18(3):737-45. Epub 2016 Mar 4.

College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.

AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.
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http://dx.doi.org/10.1208/s12248-016-9876-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256597PMC
May 2016

A phase I pharmacodynamic study of GTI-2040, an antisense oligonucleotide against ribonuclotide reductase, in acute leukemias: a California Cancer Consortium study.

Leuk Lymphoma 2016 10 19;57(10):2307-14. Epub 2016 Feb 19.

a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;

We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide reductase mRNA, on a novel dosing schedule of days 1-4 and 15-18 by continuous infusion to examine efficacy and tolerability in patients with leukemia. A dose of 11 mg/kg/d was safely reached. Dose-limiting toxicities (DLTs) at the higher levels included elevated troponin I and liver function enzymes. There were no objective responses to GTI-2040 in this study; 7/24 patients were able to complete the predetermined three infusion cycles. Pharmacokinetic and pharmacodynamic studies were performed, indicating a trend towards increasing intracellular drug levels and decreasing RRM2 gene expression with increasing doses. This dose schedule may be considered if appropriate combinations are identified in preclinical studies.
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http://dx.doi.org/10.3109/10428194.2016.1146947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969190PMC
October 2016

CD33-Targeted Lipid Nanoparticles (aCD33LNs) for Therapeutic Delivery of GTI-2040 to Acute Myelogenous Leukemia.

Mol Pharm 2015 Jun 28;12(6):2010-8. Epub 2015 Apr 28.

†Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.

CD33-targeted lipid nanoparticles (aCD33LNs) were synthesized for delivery of GTI-2040, an antisense oligonucleotide (ASO) against the R2 subunit of ribonucleotide reductase, to acute myelogenous leukemia (AML). These LNs incorporated a deoxycholate-polyethylenimine (DOC-PEI) conjugate, which has shown significant activity to facilitate oligonucleotide delivery. Anti-CD33 scFv (aCD33) was added as a targeting ligand. The delivery efficiency of this system was investigated both in vitro and in vivo. When cells were treated with aCD33LN/GTI-2040, significant uptake was observed in CD33 positive Kasumi-1 cells. aCD33LNs loaded with GTI-2040 induced significant down-regulation of R2 mRNA and protein levels in AML cells. Moreover, aCD33LN/GTI-2040 showed a 15-fold reduction in the IC50 of antileukemic drug Ara-C in Kasumi-1 cells. In Kasumi-1 xenograft model, aCD33LN/GTI-2040 showed significant R2 downregulation compared to LN/GTI-2040. Furthermore, aCD33LN/GTI-2040 coadministered with Ara-C was shown to be highly effective in tumor growth inhibition and to greatly increase survival time of mice bearing Kasumi-1 xenograft tumors. The conjugate DOC-PEI has shown an ability to include calcein release from lipid nanoparticles, suggesting a potential mechanism contributing to efficient endosome release by DOC-PEI2K. These results indicate that aCD33LNs are a highly effective vehicle for the therapeutic delivery of antisense agents to AML.
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http://dx.doi.org/10.1021/mp5008212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962870PMC
June 2015

Pulse wave velocity involving proximal portions of the aorta correlates with the degree of aortic dilatation at the sinuses of valsalva in ascending thoracic aortic aneurysms.

Ann Vasc Dis 2014 25;7(4):404-9. Epub 2014 Dec 25.

Department of Surgery, University of British Columbia , Vancouver, Canada.

Objective: To determine the relationship between arterial stiffness measured in different aortic segments and the presence and extent of ascending thoracic aortic aneurysm (ATAA).

Methods: Patients at a Thoracic Aortic Diseases clinic at a University teaching hospital were compared to patients attending a Cardiology outpatient Clinic at the same institution. A non-invasive measure of vascular stiffness was performed using pulse wave velocity (PWV) measurement of several vascular segments-carotid-femoral pulse wave velocity (cfPWV), heart-femoral pulse wave velocity (hfPWV) and brachial-ankle pulse wave velocity (baPWV). Aortic dimensions were measured on echocardiogram.

Results: Patients with ATAA (N = 32) were 66 years and the same age as those without ATAA (N = 46). There was no significant difference between those with or without aortic aneurysm with respect to cfPWV, hfPWV or baPWV. In ATAA, there was a significant (p <0.05) inverse correlation between aortic diameter at the sinuses of Valsalva and cfPWV, as well as hfPWV, but not with baPWV. This relationship was not evident in persons without ATAA.

Conclusion: Reduced aortic stiffness (increased compliance), assessed by cfPWV or hfPWV, correlates with larger aortic size of ATAA at the level of the sinuses of Valsalva but not at the ascending aorta, suggesting cfPWV may be a useful method to assess the size of ATAA at the level of the sinuses of Valsalva. Overall aortic stiffness assessed by PWV did not differentiate persons with or without an ATAA, in individuals who do not have a genetic or inheritable cause of their ATAA.
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http://dx.doi.org/10.3400/avd.oa.14-00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293191PMC
January 2015

First-line beta-blockers versus other antihypertensive medications for chronic type B aortic dissection.

Cochrane Database Syst Rev 2014 Feb 26(2):CD010426. Epub 2014 Feb 26.

Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

Background: Thoracic aortic dissection (TAD) is a severe and often lethal complication in people with hypertension. Current practice in the treatment of chronic type B aortic dissections is the use of beta-blockers as first-line therapy to decrease aortic wall stress. Other antihypertensive medications, such as calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), have been suggested for the medical therapy of type B TAD.

Objectives: To assess the effects of first-line beta-blockers compared with other first-line antihypertensive drug classes for treating chronic type B TAD.

Search Methods: We searched the Database of Abstracts of Reviews of Effects (DARE) for related reviews. We searched the Hypertension Group Specialised Register (1946 to 26 January 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 1), MEDLINE (1946 to 24 January 2014), MEDLINE In-Process, EMBASE (1974 to 24 January 2014) and ClinicalTrials.gov (to 26 January 2014).

Selection Criteria: We considered randomized controlled trials (RCTs) comparing different antihypertensive medications in the treatment of chronic type B TAD to be eligible for inclusion. Total mortality rate was the primary outcome of this review. Secondary outcomes included total non-fatal adverse events relating to TADs and number of people not requiring surgical treatment.

Data Collection And Analysis: Two review authors (KC, PL) independently reviewed titles and abstracts and decided on studies to include based on the inclusion criteria. We resolved discrepancies between the two review authors by discussion.

Main Results: After a thorough review of the search results, we identified no studies that met the inclusion criteria.

Authors' Conclusions: We did not find any RCTs that compared first-line beta-blockers with other first-line antihypertensive medications for the treatment of chronic type B TAD. Therefore, there is no RCT evidence to support the current guidelines recommending the use of beta-blockers. RCTs are required to assess the benefits and harms of beta-blockers and other antihypertensive medications as first-line treatment of chronic type B TAD.
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http://dx.doi.org/10.1002/14651858.CD010426.pub2DOI Listing
February 2014

Increasing prevalence of hypertension among patients with thoracic aorta dissection: trends over eight decades--a structured meta-analysis.

Am J Hypertens 2014 Jul 12;27(7):907-17. Epub 2014 Feb 12.

University of British Columbia, Department of Medicine-Cardiology, Vancouver, British Columbia, Canada.

Background: This structured metaanalysis focused on determining the relationship between hypertension (HTN) and thoracic aortic dissection (TAD).

Methods: Electronic searches were conducted using the MedLine database, for the period 1946 through May 2013, and manual searches from reference lists. Demographic data, patient diagnosis, and HTN prevalence were extracted from each study. Data were analyzed using weighted averages, metaanalysis, analysis of variance, trend analysis, and multivariate analysis.

Results: A total of 8,086 cases of TAD from 75 studies over eight decades were assessed. Overall prevalence of HTN in TAD was 66.7% ± 17.5%. An increase of approximately 5.6% in HTN prevalence in TAD cases occurred in every decade. Prevalence of HTN in type A dissections steadily increased, with an overall prevalence of 64.8% ± 21.3%, while in type B dissections, prevalence abruptly increased from 1950 to 1970 and remained constant thereafter, with an overall prevalence of 78.7% ± 8.6%. Trend analysis demonstrated significant (P < 0.001) and linear increasing trends for the prevalence of HTN and age at presentation. Multivariate analysis demonstrated that a history of HTN was significantly (P < 0.001) associated with increasing trends of over time, which was independent of the relationship between age and TAD.

Conclusions: The proportion of TAD patients with HTN has been increasing over eight decades. Age at presentation of TAD has also been incrementally increasing, but the increase in HTN was independent of age in multivariate analysis. The trend for increasing HTN prevalence was more evident in type A TAD. These data highlight a need to focus on HTN management in patients with thoracic aortic aneurysm.
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http://dx.doi.org/10.1093/ajh/hpt293DOI Listing
July 2014

Phase I study of GTI-2040, a ribonucleotide reductase antisense, with high dose cytarabine in patients with relapsed/refractory acute myeloid leukemia.

Leuk Lymphoma 2014 Jun 1;55(6):1332-6. Epub 2013 Nov 1.

Division of Hematology, Department of Medicine.

We hypothesized that GTI-2040, a 20-mer oligonucleotide complementary to the R2 subunit mRNA of ribonucleotide reductase, combined with high dose cytarabine (HiDAC) would result in enhanced cytotoxicity by favoring Ara-CTP DNA incorporation. In a phase I dose escalation trial, adults (≥ 60 years) with refractory or relapsed acute myeloid leukemia (AML) received daily HiDAC plus infusional GTI-2040. Using a novel assay, evidence of intracellular drug accumulation and target R2 down-regulation was observed. GTI-2040/HiDAC can be administered safely. However, with no complete remissions observed, alternative doses and schedules may need to be investigated to achieve clinical activity in older patients with AML.
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http://dx.doi.org/10.3109/10428194.2013.838764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298748PMC
June 2014

LC-MS/MS quantification of a neuropeptide fragment kisspeptin-10 (NSC 741805) and characterization of its decomposition product and pharmacokinetics in rats.

J Chromatogr B Analyt Technol Biomed Life Sci 2013 May 4;926:1-8. Epub 2013 Mar 4.

College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

The kisspeptins are critical regulators of mammalian reproduction. Kisspeptin-10 ((45)YNWNSFGLRF-NH2(54), kisspeptin-112-121 or metastin 45-54, NSC 741805), an active fragment of kisspeptin, has been shown to be a potent stimulator of gonadotropin-releasing hormone and secretion of luteinizing hormone in both rodents and primates. This shorter peptide fragment may have clinical utility potential and it is important to characterize its pharmacokinetic property. Recently, the pharmacokinetics of both kisspeptin-54 and kisspeptin-10 were characterized in humans using a radioimmunoassay (RIA), which measures only the immunoreactive kisspeptin (kisspeptin-IR). In this study, a highly sensitive and specific LC-MS/MS assay was developed to quantify kisspeptin-10 levels in rat plasma. The lower limit of quantitation (LLOQ) was 0.5 ng/mL, the within-day and between-day coefficient of variations (CVs) ranged from 5.2 to 15.4% and 1.3 to 14.2%, and the accuracy values ranged from 98 to 114% and 99 to 105%, respectively. With this method, stability studies demonstrated that kisspeptin-10 degraded rapidly with decomposition half-lives of 6.8 min, 2.9 min and 1.7 min at 4 °C, 25 °C, and 37 °C, respectively. The principal decomposition product was characterized as the N-terminal tyrosine deleted kisspeptin-10 (46)NWDSFGLRF-NH2(54). Pharmacokinetic study in rats showed that low ng/mL kisspeptin-10 was detected in the first few minutes, and eliminated rapidly and became undetectable 30 min after intravenous (i.v.) bolus administration of 1.0 mg/kg kisspeptin-10.
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http://dx.doi.org/10.1016/j.jchromb.2013.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955120PMC
May 2013

Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia.

Clin Cancer Res 2013 May 14;19(9):2355-67. Epub 2013 Mar 14.

Molecular, Cellular and Developmental Biology, The Ohio State University, Columbus, Ohio 43210, USA.

Purpose: miR-29b directly or indirectly targets genes involved in acute myeloid leukemia (AML), namely, DNMTs, CDK6, SP1, KIT, and FLT3. Higher miR-29b pretreatment expression is associated with improved response to decitabine and better outcome in AML. Thus, designing a strategy to increase miR-29b levels in AML blasts may be of therapeutic value. However, free synthetic miRs are easily degraded in bio-fluids and have limited cellular uptake. To overcome these limitations, we developed a novel transferrin-conjugated nanoparticle delivery system for synthetic miR-29b (Tf-NP-miR-29b).

Experimental Design: Delivery efficiency was investigated by flow cytometry, confocal microscopy, and quantitative PCR. The expression of miR-29b targets was measured by immunoblotting. The antileukemic activity of Tf-NP-miR-29b was evaluated by measuring cell proliferation and colony formation ability and in a leukemia mouse model.

Results: Tf-NP-miR-29b treatment resulted in more than 200-fold increase of mature miR-29b compared with free miR-29b and was approximately twice as efficient as treatment with non-transferrin-conjugated NP-miR-29b. Tf-NP-miR-29b treatment significantly downregulated DNMTs, CDK6, SP1, KIT, and FLT3 and decreased AML cell growth by 30% to 50% and impaired colony formation by approximately 50%. Mice engrafted with AML cells and then treated with Tf-NP-miR-29b had significantly longer survival compared with Tf-NP-scramble (P = 0.015) or free miR-29b (P = 0.003). Furthermore, priming AML cell with Tf-NP-miR-29b before treatment with decitabine resulted in marked decrease in cell viability in vitro and showed improved antileukemic activity compared with decitabine alone (P = 0.001) in vivo.

Conclusions: Tf-NP effectively delivered functional miR-29b, resulting in target downregulation and antileukemic activity and warrants further investigation as a novel therapeutic approach in AML.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644023PMC
May 2013

Curcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia.

PLoS One 2013 13;8(2):e55934. Epub 2013 Feb 13.

Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.

Bioactive components from dietary supplements such as curcumin may represent attractive agents for cancer prevention or treatment. DNA methylation plays a critical role in acute myeloid leukemia (AML) development, and presents an excellent target for treatment of this disease. However, it remains largely unknown how curcumin, a component of the popular Indian spice turmeric, plays a role in DNA hypomethylation to reactivate silenced tumor suppressor genes and to present a potential treatment option for AML. Here we show that curcumin down-regulates DNMT1 expression in AML cell lines, both in vitro and in vivo, and in primary AML cells ex vivo. Mechanistically, curcumin reduced the expression of positive regulators of DNMT1, p65 and Sp1, which correlated with a reduction in binding of these transcription factors to the DNMT1 promoter in AML cell lines. This curcumin-mediated down-regulation of DNMT1 expression was concomitant with p15(INK4B) tumor suppressor gene reactivation, hypomethylation of the p15(INK4B) promoter, G1 cell cycle arrest, and induction of tumor cell apoptosis in vitro. In mice implanted with the human AML MV4-11 cell line, administration of curcumin resulted in remarkable suppression of AML tumor growth. Collectively, our data indicate that curcumin shows promise as a potential treatment for AML, and our findings provide a basis for future studies to test the clinical efficacy of curcumin - whether used as a single agent or as an adjuvant - for AML treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055934PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572185PMC
August 2013

In vivo quantification of active decitabine-triphosphate metabolite: a novel pharmacoanalytical endpoint for optimization of hypomethylating therapy in acute myeloid leukemia.

AAPS J 2013 Jan 22;15(1):242-9. Epub 2012 Nov 22.

Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

Decitabine (DAC) is used for treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Following cellular uptake, DAC is activated to DAC-triphosphate (TP) and incorporated into DNA. Once incorporated into the DNA, DAC-TP binds and inactivates DNA methyltransferases (DNMTs), thereby leading to hypomethylation and re-expression of epigenetically silenced tumor suppressor genes and ultimately antileukemia activity. However, direct evidence of in vivo DAC-TP occurrence in DAC-treated patients has been difficult to demonstrate due to a lack of suitable validated analytical methodology. Thus, we developed and validated a nonradioactive sensitive and specific LC-MS/MS assay for quantification of DAC-TP. The assay is linear from 50 to 1,000 nM and from 1 to 10 μM and has a lower limit of quantitation of 50 nM and a coefficient of variation for both within- and between-day precision <20%. Following DAC treatment, we detected DAC-TP in parental and DAC-resistant AML cells (in vitro) and bone marrow (BM) and spleen of normal and leukemic mice (in vivo). Downregulation of DNMTs and correlation of DAC-TP concentration with proteins involved in mechanisms of DAC resistance were also demonstrated. The clinical applicability of this method was proven by measuring DAC-TP level in BM and blood mononuclear cells from DAC-treated AML patients. Higher levels are seemingly associated with clinical response. Monitoring the DAC-TP intracellular level may serve as a novel pharmacological endpoint for designing more effective DAC-based regimens.
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http://dx.doi.org/10.1208/s12248-012-9427-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535094PMC
January 2013

Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia.

Blood 2013 Jan 19;121(1):136-47. Epub 2012 Nov 19.

Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.

Several RNA-targeted therapeutics, including antisense oligonucleotides (ONs), small interfering RNAs, and miRNAs, constitute immunostimulatory CpG motifs as an integral part of their design. The limited success with free antisense ONs in hematologic malignancies in recent clinical trials has been attributed to the CpG motif-mediated, TLR-induced prosurvival effects and inefficient target modulation in desired cells. In an attempt to diminish their off-target prosurvival and proinflammatory effects and specific delivery, as a proof of principle, in the present study, we developed an Ab-targeted liposomal delivery strategy using a clinically relevant CD20 Ab (rituximab)-conjugated lipopolyplex nanoparticle (RIT-INP)- and Bcl-2-targeted antisense G3139 as archetypical antisense therapeutics. The adverse immunostimulatory responses were abrogated by selective B cell-targeted delivery and early endosomal compartmentalization of G3139-encapsulated RIT-INPs, resulting in reduced NF-κB activation, robust Bcl-2 down-regulation, and enhanced sensitivity to fludarabine-induced cytotoxicity. Furthermore, significant in vivo therapeutic efficacy was noted after RIT-INP-G3139 administration in a disseminated xenograft leukemia model. The results of the present study demonstrate that CD20-targeted delivery overcomes the immunostimulatory properties of CpG-containing ON therapeutics and improves efficient gene silencing and in vivo therapeutic efficacy for B-cell malignancies. The broader implications of similar approaches in overcoming immunostimulatory properties of RNA-directed therapeutics in hematologic malignancies are also discussed.
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http://dx.doi.org/10.1182/blood-2012-01-407742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538326PMC
January 2013

Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation.

Cancer Cell 2012 Nov;22(5):645-55

Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.

How inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here, we show that prolonged in vitro exposure of wild-type (WT) LGL to IL-15 results in Myc-mediated upregulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-κBp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting that reverses miR-29b repression cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.
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http://dx.doi.org/10.1016/j.ccr.2012.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627362PMC
November 2012

Reactivation of RASSF1A in breast cancer cells by curcumin.

Nutr Cancer 2012 12;64(8):1228-35. Epub 2012 Nov 12.

College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA.

Reactivation of tumor suppressor genes (TSGs) involved in carcinogenesis by nontoxic bioactive food component represents a promising strategy for cancer chemoprevention. Recently, curcumin has been demonstrated to inhibit a bacterial DNA methyltransferase (M. Sss I) activity, induce global DNA hypomethylation in leukemia cells, and reactivate several hypermethylation silenced genes in lung and prostate cancer cells. Herein, we demonstrated that curcumin can enhance the mRNA and protein levels of ras-association domain family protein 1A (RASSF1A), 1 hypermethylation-silenced TSG, and decrease its promoter methylation in breast cancer cells. Mechanistic study demonstrated that curcumin can decrease DNA methylation activity of nuclear extract and downregulate the mRNA and protein levels of DNMT1 in MCF-7 cells, which may be associated with curcumin-induced disruption of NF-κB/Sp1 complex bound to the promoter region of DNMT1. Altogether, this study reveals a novel molecular mechanism of curcumin as a chemo-preventive agent for breast cancer through hypomethylation reactivation of RASSF1A.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082258PMC
http://dx.doi.org/10.1080/01635581.2012.717682DOI Listing
May 2013

Determination of cellular uptake and intracellular levels of Cenersen (Aezea(®), EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells.

J Pharm Biomed Anal 2012 Dec 19;71:228-32. Epub 2012 Aug 19.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

TP53 encodes for tumor protein p53. The suppression of p53 protein results in interruption of DNA repair mechanisms in dividing malignant cells thereby increasing the DNA damage and activating p53-independent mechanisms of apoptosis. This ultimately may translate into enhanced cytotoxic effects of standard chemotherapy. Based on this rationale, Cenersen, a phosphorothioate oligonucleotide antisense to p53-mRNA was synthesized and tested in clinical trials for patients with acute myeloid leukemia (AML). An important component of Cenersen clinical development is to develop a sensitive and specific method to quantify plasma and intracellular levels of Cenersen in different biologic matrices in order to determine tissue and intracellular distribution of the parent compound and its metabolites. Ultimately, this will allow us to determine pharmacokinetic and pharmacodynamic relationship for dose-effect correlation and design effective regimen to be rapidly translate into the clinic. An ELISA-based assay was adapted for assay development and validation of Cenersen in mouse plasma and cell lysate. Cellular uptake of Cenersen was studied in MV4-11 and KASUMI-1 AML cell lines. Real-time RT-PCR was used to measure P53-mRNA expression changes in treated cells. The assay had a limit of quantification of 35pmol/L in mouse plasma. Within-day and between-day precision of <15% and accuracy nearly 100% were observed in a linear range of 10-2000pmol/L (R(2)=0.99) in AML cell lysate. The selectivity of this assay examined as cross-reactivity with its 3'N-1, 3'N-2-metabolites, was 16.8% and 0.4%, respectively, and with its mismatch and the scramble oligonucleotides was 0.06% and 0.4%, respectively. Cenersen was stable in mouse plasma up to 8h at 37°C. When exposed to 0.1-1μmol/L Cenersen, MV4-11 and KASUMI-1 cells showed intracellular concentration in the range of 9.97-45.34nmol/mg protein and 0.1-2.1nmol/mg protein, respectively. Successful downregulation of p53-mRNA expression was observed in Cenersen treated cells. This ELISA-based assay was applicable to plasma and intracellular concentration measurement of Cenersen. Assessment of achievable concentration of Cenersen in different biologic matrices will be useful to elucidate the biological and clinical activity of this promising drug and define its recommended dose in future clinical trials.
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http://dx.doi.org/10.1016/j.jpba.2012.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201859PMC
December 2012

A 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 2012 Jul 26;900:89-93. Epub 2012 May 26.

Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province 310022, China.

Curcumin is a widely used herbal medicine for various human diseases including inflammation and cancer. The demonstration and optimization of curcumin's activities in the clinical setting, however, have been compromised by its poor bioavailability and the lack of analytic methods to monitor its absorption. In this paper, we report the first validated liquid chromatography-tandem mass spectrometric method for simultaneous quantification of curcumin and its major metabolite: curcumin-O-glucuronide (COG), in the linear range of 2.0-2000 ng/mL in human plasma. The intra-day and inter-day accuracies of curcumin and COG in human plasma were in the range of 91.3-111.5% and 82.7-109.2% and their co-efficiency of variations were in the range of 3.5-12.7% and 3.1-11.3%, respectively. This method was capable of detecting only COG in human plasma samples from two healthy volunteers after an oral ingestion of curcumin.
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http://dx.doi.org/10.1016/j.jchromb.2012.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387345PMC
July 2012

Synthetic microRNA cassette dosing: pharmacokinetics, tissue distribution and bioactivity.

Mol Pharm 2012 Jun 23;9(6):1638-44. Epub 2012 May 23.

Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210,United States.

MicroRNAs (miRs) are deregulated in cancer and leukemia. Restoring aberrantly downregulated tumor suppressor miRs or antagonizing overexpressed oncogenic miRs in malignant cells by synthetic RNA oligonucleotides represents a potentially novel therapeutic approach in cancer and leukemia. However, given the complex networking and concurrent deregulation of miRs in malignant cells, an effective approach may require concurrent targeting of multiple miRs. Cassette dosing involves simultaneous administration of a mixture of oligonucleotides from the same or different structural classes. However, information on cassette dosing pharmacokinetics, tissue distribution and bioactivity of synthetic miRs is lacking. In this study, three synthetic 2'-methoxyphosphorothioate-miRs (2'-MeOPSmiR16-1, 2'-MeOPSmiR29b and 2'-MeOPSantagomiR155) were administered iv to C57BL/6 mice as a mixture, each at 7.5 mg/kg. Analysis of concentrations of individual miR in plasma and major organ tissues (bone marrow, spleen, liver, brain, heart, kidney and lung) was performed. The mRNA and protein levels of miR's biotargets were monitored sequentially after dosing up to 24 h. Our results demonstrated that these synthetic miRs retain their different individual pharmacokinetic properties and all display three-compartmental pharmacokinetics. 2'-MeOPSmiR16-1 has the longest plasma gamma half-life of 2508 min and lowest total body clearance of 0.0054 L/min·kg, whereas 2'-MeOPSmiR29b has the shortest gamma half-life of 510.6 min and highest total body clearance of 0.042 L/min·kg. The tissue concentrations of all three 2'-MeOPS-modified miR(s)/antagomiR were measurable from 5 min to at least 24 h after dosing, indicating that these concurrently delivered oligonucleotides can reach organ tissues. Importantly, there were biological activities of the concurrently administered miRs which persisted, as shown by the downregulation of specific targets in tested tissues, albeit with variations. Brain was one of the most sensitive tissues with respect to downregulation of mRNA and protein levels of four measured biotargets (e.g., Bcl-2, Mcl-1, DNMT3a and DNMT3b) despite its relatively low miR/antagomiRs levels. We conclude that cassette dosing is applicable to 2'-MeOPS-modified synthetic miRs that are tissue-deliverable and biofunctional without any additional formulation requirement. This study supports future exploration of miR-involved combination therapies.
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http://dx.doi.org/10.1021/mp2006483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977775PMC
June 2012

Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.

Blood 2012 Jun 7;119(25):6025-31. Epub 2012 May 7.

Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, B310 Starling-Loving Hall, Columbus, OH 43210, USA.

We recently reported promising clinical activity for a 10-day regimen of decitabine in older AML patients; high miR-29b expression associated with clinical response. Subsequent preclinical studies with bortezomib in AML cells have shown drug-induced miR-29b up-regulation, resulting in loss of transcriptional activation for several genes relevant to myeloid leukemogenesis, including DNA methyltransferases and receptor tyrosine kinases. Thus, a phase 1 trial of bortezomib and decitabine was developed. Nineteen poor-risk AML patients (median age 70 years; range, 32-84 years) enrolled. Induction with decitabine (20 mg/m(2) intravenously on days 1-10) plus bortezomib (escalated up to the target 1.3 mg/m(2) on days 5, 8, 12, and 15) was tolerable, but bortezomib-related neuropathy developed after repetitive cycles. Of previously untreated patients (age ≥ 65 years), 5 of 10 had CR (complete remission, n = 4) or incomplete CR (CRi, n = 1); 7 of 19 overall had CR/CRi. Pharmacodynamic analysis showed FLT3 down-regulation on day 26 of cycle 1 (P = .02). Additional mechanistic studies showed that FLT3 down-regulation was due to bortezomib-induced miR-29b up-regulation; this led to SP1 down-regulation and destruction of the SP1/NF-κB complex that transactivated FLT3. This study demonstrates the feasibility and preliminary clinical activity of decitabine plus bortezomib in AML and identifies FLT3 as a novel pharmacodynamic end point for future trials.
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http://dx.doi.org/10.1182/blood-2012-03-413898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383015PMC
June 2012

RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia.

Blood 2012 May 19;119(22):5229-38. Epub 2012 Apr 19.

Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

5-Azacytidine (5-azaC) is an azanucleoside approved for myelodysplastic syndrome. Approximately 80%-90% of 5-azaC is believed to be incorporated into RNA, which disrupts nucleic acid and protein metabolism leading to apoptosis. A smaller fraction (10%-20%) of 5-azaC inhibits DNA methylation and synthesis through conversion to decitabine triphosphate and subsequent DNA incorporation. However, its precise mechanism of action remains unclear. Ribonucleotide reductase (RR) is a highly regulated enzyme comprising 2 subunits, RRM1 and RRM2, that provides the deoxyribonucleotides required for DNA synthesis/repair. In the present study, we found for the first time that 5-azaC is a potent inhibitor of RRM2 in leukemia cell lines, in a mouse model, and in BM mononuclear cells from acute myeloid leukemia (AML) patients. 5-azaC-induced RRM2 gene expression inhibition involves its direct RNA incorporation and an attenuated RRM2 mRNA stability. Therefore, 5-azaC causes a major perturbation of deoxyribonucleotide pools. We also demonstrate herein that the initial RR-mediated 5-azaC conversion to decitabine is terminated through its own inhibition. In conclusion, we identify RRM2 as a novel molecular target of 5-azaC in AML. Our findings provide a basis for its more widespread clinical use either alone or in combination.
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http://dx.doi.org/10.1182/blood-2011-11-382226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369613PMC
May 2012

Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine.

Blood 2012 Feb 7;119(5):1240-7. Epub 2011 Dec 7.

Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2μM administered 2×/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy.
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http://dx.doi.org/10.1182/blood-2011-08-371690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277356PMC
February 2012

Large and small artery endothelial dysfunction in chronic fatigue syndrome.

Int J Cardiol 2012 Feb 10;154(3):335-6. Epub 2011 Nov 10.

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http://dx.doi.org/10.1016/j.ijcard.2011.10.030DOI Listing
February 2012

Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice.

Cancer Chemother Pharmacol 2012 Mar 4;69(3):679-89. Epub 2011 Oct 4.

College of Pharmacy, The Ohio State University, Room 152, Riffe Building, 500 W. 12th Avenue, Columbus, OH 43210, USA.

Purpose: Curcumin has shown a variety of biological activity for various human diseases including cancer in preclinical setting. Its poor oral bioavailability poses significant pharmacological barriers to its clinical application. Here, we established a practical nano-emulsion curcumin (NEC) containing up to 20% curcumin (w/w) and conducted the pharmacokinetics of curcuminoids and curcumin metabolites in mice.

Methods: This high loading NEC was formulated based on the high solubility of curcumin in polyethylene glycols (PEGs) and the synergistic enhancement of curcumin absorption by PEGs and Cremophor EL. The pharmacokinetics of curcuminoids and curcumin metabolites was characterized in mice using a LC-MS/MS method, and the pharmacokinetic parameters were determined using WinNonlin computer software.

Results: A tenfold increase in the AUC (0→24h) and more than 40-fold increase in the C (max) in mice were observed after an oral dose of NEC compared with suspension curcumin in 1% methylcellulose. The plasma pharmacokinetics of its two natural congeners, demethoxycurcumin and bisdemethoxycurcumin, and three metabolites, tetrahydrocurcumin (THC), curcumin-O-glucuronide, and curcumin-O-sulfate, was characterized for the first time in mice after an oral dose of NEC.

Conclusion: This oral absorption enhanced NEC may provide a practical formulation to conduct the correlative study of the PK of curcuminoids and their pharmacodynamics, e.g., hypomethylation activity in vivo.
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http://dx.doi.org/10.1007/s00280-011-1749-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368221PMC
March 2012

Phase 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 2011 Sep 8;29(25):3427-34. Epub 2011 Aug 8.

The Ohio State University, Columbus, OH 43210, USA.

Purpose: Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM.

Patients And Methods: A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions.

Results: Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate.

Conclusion: The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.
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http://dx.doi.org/10.1200/JCO.2010.32.4962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164245PMC
September 2011

CCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability.

Cancer Res 2011 Jul 18;71(14):4866-76. Epub 2011 May 18.

Division of Pharmaceutical Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

The cell-cycle G(2)-M phase gene UBE2C is overexpressed in various solid tumors including castration-resistant prostate cancer (CRPC). Our recent studies found UBE2C to be a CRPC-specific androgen receptor (AR) target gene that is necessary for CRPC growth, providing a potential novel target for therapeutic intervention. In this study, we showed that the G(1)-S cell-cycle inhibitor-779 (CCI-779), an mTOR inhibitor, inhibited UBE2C mRNA and protein expression in AR-positive CRPC cell models abl and C4-2B. Treatment with CCI-779 significantly decreased abl cell proliferation in vitro and in vivo through inhibition of cell-cycle progression of both G(2)-M and G(1)-S phases. In addition, exposure of abl and C4-2B cells to CCI-779 also decreased UBE2C-dependent cell invasion. The molecular mechanisms for CCI-779 inhibition of UBE2C gene expression involved a decreased binding of AR coactivators SRC1, SRC3, p300, and MED1 to the UBE2C enhancers, leading to a reduction in RNA polymerase II loading to the UBE2C promoter, and attenuation of UBE2C mRNA stability. Our data suggest that, in addition to its ability to block cell-cycle G(1) to S-phase transition, CCI-779 causes a cell-cycle G(2)-M accumulation and an inhibition of cell invasion through a novel UBE2C-dependent mechanism, which contributes to antitumor activities of CCI-779 in UBE2C overexpressed AR-positive CRPC.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-4576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138908PMC
July 2011

Effects of human oral mucosal tissue, saliva, and oral microflora on intraoral metabolism and bioactivation of black raspberry anthocyanins.

Cancer Prev Res (Phila) 2011 Aug 10;4(8):1209-21. Epub 2011 May 10.

Division of Oral Maxillofacial Surgery, Pathology & Anesthesiology, College of Dentistry, 2191B Postle Hall, 305 W. 12th Ave, The Ohio State University, Columbus, OH 43210, USA.

Our oral cancer chemoprevention trial data implied that patient-specific differences in local retention and metabolism of freeze-dried components of black raspberries (BRB) affected therapeutic responsiveness. Subsequent studies have confirmed that anthocyanins are key contributors to BRB's chemopreventive effects. Consequently, functional assays, immunoblotting, and immunohistochemical analyses to evaluate levels and distribution of BRB anthocyanin-relevant metabolic enzymes in human oral tissues were conducted. Liquid chromatography/tandem mass spectrometry (LC/MS-MS) analyses of time course saliva samples collected following BRB rinses were conducted to assess local pharmacokinetics and compare the capacities of three different BRB rinse formulations to provide sustained intraoral levels of anthocyanins. Protein profiles showed the presence of key metabolic enzymes in all 15 oral mucosal tissues evaluated, whereas immunohistochemistry confirmed these enzymes were distributed within surface oral epithelia and terminal salivary ducts. β-Glucosidase assays confirmed that whole and microflora-reduced saliva can deglycosylate BRB anthocyanins, enabling generation of the bioactive aglycone, cyanidin. LC/MS-MS analyses showed retention of parent anthocyanins and their functional, stable metabolite, protocatechuic acid, in saliva for up to 4 hours after rinsing. Furthermore, postrinse saliva samples contained glucuronidated anthocyanin conjugates, consistent with intracellular uptake and phase II conversion of BRB anthocyanins into forms amenable to local recycling. Our data show that comparable to the small intestine, the requisite hydrolytic, phase II and efflux transporting enzymes necessary for local enteric recycling are present and functional in human oral mucosa. Notably, interpatient differences in anthocyanin bioactivation and capacities for enteric recycling would impact treatment as retention of bioactivated chemopreventives at the target site would sustain therapeutic effectiveness.
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http://dx.doi.org/10.1158/1940-6207.CAPR-11-0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151333PMC
August 2011

Resistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells.

AAPS J 2011 Sep 4;13(3):357-64. Epub 2011 May 4.

College of Pharmacy, The Ohio State University, Columbus, USA.

Protein synthesis is a powerful therapeutic target in leukemias and other cancers, but few pharmacologically viable agents are available that affect this process directly. The plant-derived agent silvestrol specifically inhibits translation initiation by interfering with eIF4A/mRNA assembly with eIF4F. Silvestrol has potent in vitro and in vivo activity in multiple cancer models including acute lymphoblastic leukemia (ALL) and is under pre-clinical development by the US National Cancer Institute, but no information is available about potential mechanisms of resistance. In a separate report, we showed that intraperitoneal silvestrol is approximately 100% bioavailable systemically, although oral doses were only 1% bioavailable despite an apparent lack of metabolism. To explore mechanisms of silvestrol resistance and the possible role of efflux transporters in silvestrol disposition, we characterized multi-drug resistance transporter expression and function in a silvestrol-resistant ALL cell line generated via culture of the 697 ALL cell line in gradually increasing silvestrol concentrations. This resistant cell line, 697-R, shows significant upregulation of ABCB1 mRNA and P-glycoprotein (Pgp) as well as cross-resistance to known Pgp substrates vincristine and romidepsin. Furthermore, 697-R cells readily efflux the fluorescent Pgp substrate rhodamine 123. This effect is prevented by Pgp inhibitors verapamil and cyclosporin A, as well as siRNA to ABCB1, with concomitant re-sensitization to silvestrol. Together, these data indicate that silvestrol is a substrate of Pgp, a potential obstacle that must be considered in the development of silvestrol for oral delivery or targeting to tumors protected by Pgp overexpression.
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http://dx.doi.org/10.1208/s12248-011-9276-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160166PMC
September 2011