JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer.
J. Clin. Oncol.
PUBLISHED: 11-19-2014
Show Abstract
Hide Abstract
Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy.
Related JoVE Video
A phase I study of TRC105 anti-CD105 (endoglin) antibody in metastatic castration-resistant prostate cancer.
BJU Int.
PUBLISHED: 11-03-2014
Show Abstract
Hide Abstract
? TRC105 is a chimeric IgG1 monoclonal antibody that binds endoglin (CD105). ? This phase I open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC).
Related JoVE Video
A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors.
Oncotarget
PUBLISHED: 10-21-2014
Show Abstract
Hide Abstract
Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.
Related JoVE Video
An Open Label Phase 1b Dose Escalation Study of TRC105 (Anti-Endoglin Antibody) with Bevacizumab in Patients with Advanced Cancer.
Clin. Cancer Res.
PUBLISHED: 09-28-2014
Show Abstract
Hide Abstract
Purpose Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essential for angiogenesis and upregulated in the setting of VEGF inhibition. TRC105 is an anti-endoglin IgG1 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, pharmacokinetics, and anti-tumor activity of TRC105 in combination with bevacizumab. Patients and Methods Patients (n=38) with advanced solid tumors, Eastern Cooperative Group performance status 0-1, and normal organ function were treated with escalating doses of TRC105 plus bevacizumab until disease progression or unacceptable toxicity using a standard 3 + 3 phase 1 design. Results TRC105 and bevacizumab were well tolerated at their recommended single agent doses (10 mg/kg) when the initial dose of TRC105 was delayed by one week and divided over two days to limit the frequency of headache. The concurrent administration of bevacizumab and TRC105 did not otherwise potentiate known toxicities of TRC105 or bevacizumab. Hypertension and proteinuria were observed, though not at rates expected for single agent bevacizumab. Several patients who had previously progressed on bevacizumab or VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) treatment experienced reductions in tumor volume, including two partial responses by RECIST, and six remained without progression for longer periods than during their prior VEGF inhibitor therapy. Conclusion TRC105 was well tolerated with bevacizumab and clinical activity was observed in a VEGF inhibitor refractory population. Ongoing clinical trials are testing TRC105 in combination with bevacizumab in glioblastoma, and with VEGFR TKIs in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma.
Related JoVE Video
Phase I Trial of Bortezomib (PS-341; NSC 681239) and "Nonhybrid" (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms.
Clin. Cancer Res.
PUBLISHED: 09-23-2014
Show Abstract
Hide Abstract
This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma).
Related JoVE Video
A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin, and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical and Translational Study.
Clin. Cancer Res.
PUBLISHED: 09-04-2014
Show Abstract
Hide Abstract
This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed.
Related JoVE Video
A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms.
Cancer Chemother. Pharmacol.
PUBLISHED: 09-03-2014
Show Abstract
Hide Abstract
To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations.
Related JoVE Video
Pharmacogenetics of membrane transporters: a review of current approaches.
Methods Mol. Biol.
PUBLISHED: 08-25-2014
Show Abstract
Hide Abstract
This chapter provides a review of the pharmacogenetics of membrane transporters, including ABC transporters and OATPs. Membrane transporters are heavily involved in drug disposition, by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have a significant effect on the absorption, distribution, metabolism, excretion, and activity of compounds. Although few drug transporter polymorphisms have transitioned from the bench to the bedside, this chapter discusses clinical development of transporter pharmacogenetic markers. Finally, development of SLCO1B1 genotyping to avoid statin induced adverse drug reactions is discussed as a model case for transporter pharmacogenetics clinical development.
Related JoVE Video
Potential novel role of bevacizumab in glioblastoma and cervical cancer.
Cancer Biol. Ther.
PUBLISHED: 07-21-2014
Show Abstract
Hide Abstract
The VEGF-A binding monoclonal antibody bevacizumab is a widely prescribed angiogenesis inhibitor and indicated for many types of cancer. As shown by three randomized phase 3 trials recently published in the New England Journal of Medicine, novel indications for this drug are still being explored. In the RTOG 0825 and AVAglio trials the effect of bevacizumab addition to standard therapy in newly diagnosed glioblastoma (radiotherapy plus temozolomide) was investigated, while in GOG 240 the combination of platinum-based chemotherapy plus bevacizumab was explored in advanced cervical cancer. In RTOG 0825, addition of bevacizumab to standard therapy did not result in survival benefit, and moreover, quality of life was more deteriorated in the bevacizumab arm. In AVAglio, however, progression-free survival (PFS) was significantly increased in the bevacizumab group and these patients also experienced a longer deterioration-free survival. These conflicting results do not fully support the incorporation of bevacizumab in the first-line treatment of glioblastoma. In contrast, in GOG 240 the bevacizumab group (including paclitaxel plus topotecan or paclitaxel) experienced a significant longer PFS and overall survival, and quality of life was not negatively affected in these patients. Thus, these results favor the use of bevacizumab in the treatment of advanced cervical cancer.
Related JoVE Video
Prostate tumor development and androgen receptor function alterations in a new mouse model with ERG overexpression and PTEN inactivation.
Cancer Biol. Ther.
PUBLISHED: 07-09-2014
Show Abstract
Hide Abstract
Gene fusions involving ETS transcription factors (predominantly ERG and ETV1) and PTEN deletions are prevalent in the prostate cancer genome. This report describes a novel mouse model that overexpresses ERG and lacks PTEN with the majority of mice developing prostate tumors by 6 mo. Biological mechanisms suggest increased/altered binding of the male hormone receptor in the genome. This model will be useful in pre-clinical evaluation of new drugs targeting these common prostate cancer genomic alterations.
Related JoVE Video
Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC-MS/MS method for clinical pharmacokinetic application.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 06-18-2014
Show Abstract
Hide Abstract
Mithramycin is a neoplastic antibiotic synthesized by various Streptomyces bacteria. It is under investigation as a chemotherapeutic treatment for a wide variety of cancers. Ongoing and forthcoming clinical trials will require pharmacokinetic analysis of mithramycin in humans, both to see if target concentrations are achieved and to optimize dosing and correlate outcomes (response/toxicity) with pharmacokinetics. Two published methods for mithramycin quantitation exist, but both are immunoassays that lack current bioanalytical standards of selectivity and sensitivity. To provide an upgraded and more widely applicable assay, a UPLC-MS/MS method for quantitation of mithramycin in human plasma was developed. Solid-phase extraction allowed for excellent recoveries (>90%) necessary for high throughput analyses on sensitive instrumentation. However, a ?55% reduction in analyte signal was observed as a result of plasma matrix effects. Mithramycin and the internal standard chromomycin were separated on a Waters Acquity BEH C18 column (2.1×50 mm, 1.7 ?m) and detected using electrospray ionization operated in the negative mode at mass transitions m/z 1083.5?268.9 and 1181.5?269.0, respectively, on an AB Sciex QTrap 5500. The assay range was 0.5-500 ng/mL and proved to be linear (r(2)>0.996), accurate (?10% deviation), and precise (CV<15%). Mithramycin was stable in plasma at room temperature for 24 h, as well as through three freeze-thaw cycles. This method was subsequently used to quantitate mithramycin plasma concentrations from patients enrolled on two clinical trials at the NCI.
Related JoVE Video
Prolonged low intensity EPOCH-rituximab has improved toxicity in Burkitt lymphoma compared with standard short, high intensity therapy.
Cancer Biol. Ther.
PUBLISHED: 06-11-2014
Show Abstract
Hide Abstract
Burkitt lymphoma is an aggressive form of non-Hodgkin lymphoma that has a short doubling time, thus intense short-cycle chemotherapy has been thought to be essential. A recent NCI-sponsored clinical trial investigated DA-EPOCH-R given to 19 HIV-negative patients and a short course regimen (SC-EPOCH-RR) given to 11 HIV-positive patients in hopes of maintaining the efficacy of the regimen while decreasing the typical side effects from the intensive short-cycle chemotherapy. Low intensity EPOCH-R based therapy achieved excellent rates of efficacy despite a significant difference in the median cumulative dose between the DA-EPOCH-R and SC-EPOCH-RR cohorts. Furthermore, both cohorts experienced mainly grade 1 and grade 2 toxicities, with SC-EPOCH-RR cohort patients experiencing less adverse events than DA-EPOCH-R cohort patients. This recent clinical investigation suggests the most important therapeutic principle is not the intensity but rather the length of exposure time above an effective threshold concentration. Since short, intense bolus doses are the standard therapy for Burkitt lymphoma, these findings are clinically relevant and significant.
Related JoVE Video
Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses.
J. Natl. Cancer Inst.
PUBLISHED: 06-01-2014
Show Abstract
Hide Abstract
Olaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.
Related JoVE Video
Multiparametric MRI in prostate cancer management.
Nat Rev Clin Oncol
PUBLISHED: 05-20-2014
Show Abstract
Hide Abstract
Prostate cancer is the second most common cancer in men worldwide. The clinical behaviour of prostate cancer ranges from low-grade indolent tumours that never develop into clinically significant disease to aggressive, invasive tumours that may progress rapidly to metastatic disease and death. Therefore, there is an urgent clinical need to detect high-grade cancers and to differentiate them from the indolent, slow-growing tumours. Conventional methods of cancer detection-such as levels of prostate-specific antigen (PSA) in serum, digital rectal examination, and random biopsies-are limited in their sensitivity, specificity, or both. The combination of conventional anatomical MRI and functional magnet resonance sequences-known as multiparametric MRI (mp-MRI)-is emerging as an accurate tool for identifying clinically relevant tumours owing to its ability to localize them. In this Review, we discuss the value of mp-MRI in localized and metastatic prostate cancer, highlighting its role in the detection, staging, and treatment planning of prostate cancer.
Related JoVE Video
New mechanism of lenalidomide activity.
Cancer Biol. Ther.
PUBLISHED: 05-19-2014
Show Abstract
Hide Abstract
Lenalidomide is an immunomodulatory agent (IMiD) that has activity in hematologic cancer (e.g., multiple myeloma). The immunomodulatory and apoptotic properties are readily apparent in therapy. However, the exact mechanism of action has been difficult to quantify until recently when it was shown that another IMiD, thalidomide, binds to an E3 ubiquitin ligase complex constituent, CRBN. The article by Kronke et al. demonstrates that, by binding to CRBN and altering its selectivity, lenalidomide potentiates the ubiquitination and proteolysis of 2 specific proteins, IKZF1 and IKZF3. An article in the same issue, by Lu et al., supports these observations. IKZF1 and IKZF3 are transcription factors that are necessary for multiple myeloma, and repression of these transcription factors is a likely mechanism for lenalidomide activity in this disease.
Related JoVE Video
Pharmacologic biomarkers in the development of stratified cancer medicine.
Clin. Cancer Res.
PUBLISHED: 05-17-2014
Show Abstract
Hide Abstract
Clinical pharmacologic research plays a vital role in cancer drug development. In recent years, biomarker studies have become integral to this process, specifically the use of pharmacologic biomarkers in the development of targeted therapies and their translation to clinical practice. In this overview, we discuss the validation of pharmacodynamics (PD) biomarkers and highlight the circulating tumor DNA as a promising cancer biomarker to illustrate how PD biomarkers can be powerful tools for guiding treatment strategies. We provide insights into PD biomarker approaches for future development of novel therapies and their role in cancer medicine. See all articles in this CCR focus section, "Progress in pharmacodynamic endpoints."
Related JoVE Video
Multi-institutional Study of Outcomes After Pediatric Heart Transplantation: Candidate Gene Polymorphism Analysis of ABCC2.
J Pediatr Pharmacol Ther
PUBLISHED: 05-01-2014
Show Abstract
Hide Abstract
Earlier studies have indicated that the pharmacokinetics of mycophenolic acid (MPA) is influenced by polymorphisms of ABCC2, which encodes for the membrane transporter MRP2. The ABCC2 rs717620 A allele has been associated with enterohepatic recirculation of MPA, and our previous work had correlated the discontinuance of MPA with this allele in pediatric heart transplant patients. Therefore, we hypothesized that the ABCC2 rs717620 A allele would be associated with poorer outcomes including rejection with hemodynamic compromise (RHC), graft failure, and death in the pediatric heart transplant (PHTx) population receiving MPA.
Related JoVE Video
Genetic variation: effect on prostate cancer.
Biochim. Biophys. Acta
PUBLISHED: 04-17-2014
Show Abstract
Hide Abstract
The crucial role of androgens in the development of prostate cancer is well established. The aim of this review is to examine the role of constitutional (germline) and tumor-specific (somatic) polymorphisms within important regulatory genes of prostate cancer. These include genes encoding enzymes of the androgen biosynthetic pathway, the androgen receptor gene, genes that encode proteins of the signal transduction pathways that may have a role in disease progression and survival, and genes involved in prostate cancer angiogenesis. Characterization of deregulated pathways critical to cancer cell growth have lead to the development of new treatments, including the CYP17 inhibitor abiraterone and clinical trials using novel drugs that are ongoing or recently completed [1]. The pharmacogenetics of the drugs used to treat prostate cancer will also be addressed. This review will define how germline polymorphisms are known affect a multitude of pathways, and therefore phenotypes, in prostate cancer etiology, progression, and treatment.
Related JoVE Video
Multiparametric magnetic resonance imaging of the prostate AIDS to detect lesion progression.
J Comput Assist Tomogr
PUBLISHED: 04-16-2014
Show Abstract
Hide Abstract
Multiparametric magnetic resonance imaging (MRI) provides an accurate anatomical assessment of the tumor and its local staging. Herein, we report a case of intermediate-risk prostatic adenocarcinoma, initially followed on active surveillance, which upgraded from Gleason 7 (3 + 4) to Gleason 8 (4 + 4) on transrectal ultrasound/MRI fusion biopsy after progression of MR spectroscopic findings and review of the role of multiparametric MRI in the follow-up of patients with prostate cancer undergoing active surveillance.
Related JoVE Video
Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma.
Clin. Immunol.
PUBLISHED: 04-10-2014
Show Abstract
Hide Abstract
Interleukin-2 receptor ? chain (CD25) is overexpressed in human T-cell leukemia virus 1 associated adult T-cell leukemia/lymphoma (ATL). Daclizumab a humanized monoclonal antibody blocks IL-2 binding by recognizing the interleukin-2 receptor ? chain (CD25). We conducted a phase I/II trial of daclizumab in 34 patients with ATL. Saturation of surface CD25 on circulating ATL cells was achieved at all doses; however saturation on ATL cells in lymph nodes required 8mg/kg. Up to 8mg/kg of daclizumab administered every 3weeks was well tolerated. No responses were observed in 18 patients with acute or lymphoma ATL; however, 6 partial responses were observed in 16 chronic and smoldering ATL patients. The pharmacokinetics/pharmacodynamics of daclizumab suggest that high-dose daclizumab would be more effective than low-dose daclizumab in treatment of lymphoid malignancies and autoimmune diseases (e.g., multiple sclerosis) since high-dose daclizumab is required to saturate IL-2R alpha in extravascular sites.
Related JoVE Video
Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1?/p300 complex in a preclinical model of prostate cancer.
Mol. Cancer
PUBLISHED: 04-02-2014
Show Abstract
Hide Abstract
The downstream targets of hypoxia inducible factor-1 alpha (HIF-1?) play an important role in tumor progression and angiogenesis. Therefore, inhibition of HIF-mediated transcription has potential in the treatment of cancer. One attractive strategy for inhibiting HIF activity is the disruption of the HIF-1?/p300 complex, as p300 is a crucial coactivator of hypoxia-inducible transcription. Several members of the epidithiodiketopiperazine (ETP) family of natural products have been shown to disrupt the HIF-1?/p300 complex in vitro; namely, gliotoxin, chaetocin, and chetomin. Here, we further characterized the molecular mechanisms underlying the antiangiogenic and antitumor effects of these ETPs using a preclinical model of prostate cancer. In the rat aortic ring angiogenesis assay, gliotoxin, chaetocin, and chetomin significantly inhibited microvessel outgrowth at a GI50 of 151, 8, and 20 nM, respectively. In vitro co-immunoprecipitation studies in prostate cancer cell extracts demonstrated that these compounds disrupted the HIF-1?/p300 complex. The downstream effects of inhibiting the HIF-1?/p300 interaction were evaluated by determining HIF-1? target gene expression at the mRNA and protein levels. Dose-dependent decreases in levels of secreted VEGF were detected by ELISA in the culture media of treated cells, and the subsequent downregulation of VEGFA, LDHA, and ENO1 HIF-1? target genes were confirmed by semi-quantitative real-time PCR. Finally, treatment with ETPs in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. These results suggest that directly targeting the HIF-1?/p300 complex with ETPs may be an effective approach for inhibiting angiogenesis and tumor growth.
Related JoVE Video
Inhibition of the HIF1?-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II).
Eur J Med Chem
PUBLISHED: 02-11-2014
Show Abstract
Hide Abstract
Protein-protein interactions between the hypoxia inducible factor (HIF) and the transcriptional coactivators p300/CBP are potential cancer targets due to their role in the hypoxic response. A natural product based screen led to the identification of indandione and benzoquinone derivatives that reduce the tight interaction between a HIF-1? fragment and the CH1 domain of p300. The indandione derivatives were shown to fragment to give ninhydrin, which was identified as the active species. Both the naphthoquinones and ninhydrin were observed to induce Zn(II) ejection from p300 and the catalytic domain of the histone demethylase KDM4A. Together with previous reports on the effects of related compounds on HIF-1? and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds.
Related JoVE Video
Androgen receptor CAG repeat length and TMPRSS2:ETS prostate cancer risk: results From the Prostate Cancer Prevention Trial.
Urology
PUBLISHED: 02-10-2014
Show Abstract
Hide Abstract
To investigate the association between the length of the polymorphic trinucleotide CAG microsatellite repeats in exon 1 of the AR gene and the risk of prostate cancer containing TMPRSS2:ETS fusion genes.
Related JoVE Video
Statin drug use is not associated with prostate cancer risk in men who are regularly screened.
J. Urol.
PUBLISHED: 01-21-2014
Show Abstract
Hide Abstract
Prospective cohort studies support the hypothesis that statin drug users have a lower risk of aggressive prostate cancer. Whether statin drug use influences the risk of screen detected disease is less clear, possibly because of complex detection biases. Thus, we investigated this association in a setting in which men had low baseline serum prostate specific antigen concentration and were screened annually.
Related JoVE Video
Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers.
J Clin Pharmacol
PUBLISHED: 01-08-2014
Show Abstract
Hide Abstract
Carriers of two copies of the loss-of-function CYP2C19*2 variant convert less clopidogrel into its active metabolite, resulting in diminished antiplatelet responses and higher cardiovascular event rates. To evaluate whether increasing the daily clopidogrel dose in poor metabolizers (PM) overcomes the effect of the CYP2C19?*?2 variant, we enrolled 18 healthy participants in a genotype-stratified, multi-dose, three-period, fixed-sequence crossover study. Six participants with the *1/*1 extensive (EM), *1/*2 intermediate (IM), and *2/*2 poor metabolizer genotypes each received 75?mg, 150 mg, and 300?mg each for 8 days. In each period, maximal platelet aggregation 4?hours post-dose (MPA4) and active metabolite area under the curve (AUC) differed among genotype groups (P?
Related JoVE Video
A sensitive and robust HPLC assay with fluorescence detection for the quantification of pomalidomide in human plasma for pharmacokinetic analyses.
J Pharm Biomed Anal
PUBLISHED: 01-02-2014
Show Abstract
Hide Abstract
Pomalidomide is a second generation IMiD (immunomodulatory agent) that has recently been granted approval by the Food and Drug Administration for treatment of relapsed multiple myeloma after prior treatment with two antimyeloma agents, including lenalidomide and bortezomib. A simple and robust HPLC assay with fluorescence detection for pomalidomide over the range of 1-500ng/mL has been developed for application to pharmacokinetic studies in ongoing clinical trials in various other malignancies. A liquid-liquid extraction from human plasma alone or pre-stabilized with 0.1% HCl was performed, using propyl paraben as the internal standard. From plasma either pre-stabilized with 0.1% HCl or not, the assay was shown to be selective, sensitive, accurate, precise, and have minimal matrix effects (<20%). Pomalidomide was stable in plasma through 4 freeze-thaw cycles (<12% change), in plasma at room temperature for up to 2h for samples not pre-stabilized with 0.1% HCl and up to 8h in samples pre-stabilized with 0.1% HCl, 24h post-preparation at 4°C (<2% change), and showed excellent extraction recovery (?90%). This is the first reported description of the freeze/thaw and plasma stability of pomalidomide in plasma either pre-stabilized with 0.1% HCl or not. The information presented in this manuscript is important when performing pharmacokinetic analyses. The method was used to analyze clinical pharmacokinetics samples obtained after a 5mg oral dose of pomalidomide. This relatively simple HPLC-FL assay allows a broader range of laboratories to measure pomalidomide for application to clinical pharmacokinetics.
Related JoVE Video
Important role of CYP2J2 in protein kinase inhibitor degradation: a possible role in intratumor drug disposition and resistance.
PLoS ONE
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
We have investigated in vitro the metabolic capability of 3 extrahepatic cytochromes P-450, CYP1A1, 1B1 and 2J2, known to be over-expressed in various tumors, to biotransform 5 tyrosine kinase inhibitors (TKI): dasatinib, imatinib, nilotinib, sorafenib and sunitinib. Moreover, mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in 6 hepatocellular and 14 renal cell carcinoma tumor tissues and their surrounding healthy tissues, was determined. Our results show that CYP1A1, 1B1 and especially 2J2 can rapidly biotransform the studied TKIs with a metabolic efficiency similar to that of CYP3A4. The mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in tumor biopsies has shown i) the strong variability of CYP expression and ii) distinct outliers showing high expression levels (esp. CYP2J2) that are compatible with high intratumoral CYP activity and tumor-specific TKI degradation. CYP2J2 inhibition could be a novel clinical strategy to specifically increase the intratumoral rather than plasma TKI levels, improving TKI efficacy and extending the duration before relapse. Such an approach would be akin to beta-lactamase inhibition, a classical strategy to avoid antibiotic degradation and resistance.
Related JoVE Video
Integrating pharmacogenetic information and clinical decision support into the electronic health record.
J Am Med Inform Assoc
PUBLISHED: 12-03-2013
Show Abstract
Hide Abstract
Pharmacogenetics (PG) examines gene variations for drug disposition, response, or toxicity. At the National Institutes of Health Clinical Center (NIH CC), a multidepartment Pharmacogenetics Testing Implementation Committee (PGTIC) was established to develop clinical decision support (CDS) algorithms for abacavir, carbamazepine, and allopurinol, medications for which human leukocyte antigen (HLA) variants predict severe hypersensitivity reactions. Providing PG CDS in the electronic health record (EHR) during order entry could prevent adverse drug events. Medical Logic Module (MLM) programming was used to implement PG CDS in our EHR. The MLM checks to see if an HLA sequence-based gene test is ordered. A message regarding test status (result present, absent, pending, or test not ordered) is displayed on the order form, and the MLM determines if the prescriber can place the order, place it but require an over-ride reason, or be blocked from placing the order. Since implementation, more than 725 medication orders have been placed for over 230 patients by 154 different prescribers for the three drugs included in our PG program. Prescribers commonly used an over-ride reason when placing the order mainly because patients had been receiving the drug without reaction before implementation of the CDS program. Successful incorporation of PG CDS into the NIH CC EHR required a coordinated, interdisciplinary effort to ensure smooth activation and a positive effect on patient care. Prescribers have adapted to using the CDS and have ordered PG testing as a direct result of the implementation.
Related JoVE Video
Urinary aHGF, IGFBP3 and OPN as diagnostic and prognostic biomarkers for prostate cancer.
Biomark Med
PUBLISHED: 11-26-2013
Show Abstract
Hide Abstract
Aim: Serum PSA screening for prostate cancer (PCa) is controversial. Here, we identify three urinary biomarkers - aHGF, IGFBP3 and OPN - for PCa screening and prognostication. Methods: Urinary aHGF, OPN and IGFBP3 from healthy men (n = 19) and men with localized (n = 65) and metastatic (n = 36) PCa were quantified via ELISA. Mann-Whitney nonparametric t-test and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analyses were used to analyze associations. Results: Mean aHGF and IGFBP3 levels were significantly elevated in PCa patients versus controls (p = 0.0006 and p = 0.0012, respectively), and the area under the curve of the receiver operating characteristic curve (indicator of diagnostic accuracy) for aHGF and IGFBP3 was 0.75 and 0.74, respectively. OPN levels were significantly higher in metastatic groups (p = 0.0060) versus localized and controls (area under the curve = 0.68). Conclusion: Urinary aHGF and IGFBP3 exhibit the capacity for diagnostic discrimination for PCa, whereas OPN may indicate presence of metastatic disease.
Related JoVE Video
The androgen receptor transcriptional program in castration-resistant prostate cancer: Cell lines vs. tissue samples.
Cancer Biol. Ther.
PUBLISHED: 11-19-2013
Show Abstract
Hide Abstract
The androgen receptor (AR) is central to the initiation and progression of prostate cancer, even after castration. Its transcriptional activity has previously been studied in cell lines. A group at the University of Cambridge recently outlined the AR transcriptional program in tissue samples, with an emphasis on castration-resistant tumors. AR binding sites, gene-expression changes (in xenografts), and potential transcription factor interactions were notably different from those observed in cultured cells. These discrepancies suggest a distinct signaling network for the AR in vivo and serve as a reminder that results from in vitro models should be checked against clinical realities.
Related JoVE Video
Prostate cancer progression attributed to autonomic nerve development: Potential for therapeutic prevention of localized and metastatic disease.
Cancer Biol. Ther.
PUBLISHED: 09-04-2013
Show Abstract
Hide Abstract
In a study recently published in Science, Magnon et al. show that both the sympathetic and parasympathetic components of the autonomic nervous system play an integral part in the development and dissemination of prostate cancer (PCa). Inhibition of the sympathetic nervous system (SNS) and disruption of the adrenergic receptors, specifically Ard? 2, resulted in the prevention of primary PCa tumor development in mice. The authors found that inhibition of the SNS is only successful in preventing murine tumor development if completed early enough, and the parasympathetic nervous system (PNS) predominates in later stages of PCa. Inhibition of the PNS by way of the cholinergic receptor, muscarinic 1 (Chrm1), caused mice to develop less metastases to the pelvic lymph nodes, intestines, and bones. A PCa progression scheme has been outlined where initial tumor engraftment is controlled by the SNS but then becomes less prominent than the PNS, which promotes metastasis. The investigators showed the dependence of the autonomic nervous system on development of PCa and present opportunities for prevention; further studies are needed to confirm these results in humans.
Related JoVE Video
A novel uHPLC-MS/MS method for the quantitation of AZD7451 (AZ12607092) in human plasma.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 08-07-2013
Show Abstract
Hide Abstract
Tropomyosin-related kinases (Trk) are tyrosine kinase receptors implicated in tumor proliferation, invasion, and survival signaling across a number of tumors, making them potentially attractive targets for the treatment of cancer. AZD7451 is a potent and selective inhibitor of Trk kinases currently undergoing a Phase I dose escalation in glioblastoma multiforme at the National Cancer Institute. A key part of early clinical testing for AZD7451 involves demonstrating that pharmacokinetic half-life and clinical exposures of AZD7451 are sufficient to inhibit Trk receptors in preclinical models. To address this need, an ultra sensitive analytical method was developed to measure the AZD7451 profile in human plasma. A liquid-liquid extraction recovered >80% of AZD7451 before quantitative analysis by ultra HPLC-MS/MS. A Varian Polaris(®) C18-A column and a mass transition of m/z 383.5?340.5 (m/z 389.6?342.0 for the internal standard [(2)H6]-AZD7451) was used, and a dynamic calibration range of 0.5-1000ng/mL was established, which provided a sensitive (<8.5% deviation), and precise (<6%) quantitative assay for AZD7451. AZD7451 demonstrated stability in human plasma at room temperature for 24h (<7% change) and after extraction at 4°C for 24h (<8% change), and was stable through 4 freeze/thaw cycles (<8% change). This method was used to measure AZD7451 plasma levels in clinical samples to confirm the sensitivity at several time points following AZD7451 treatment in subjects with glioblastoma.
Related JoVE Video
Uncovering the genetic landscape driving castration-resistant prostate cancer.
Cancer Biol. Ther.
PUBLISHED: 08-07-2013
Show Abstract
Hide Abstract
Identification of the mechanisms that drive progression of metastatic castration-resistant prostate cancer (CRPC) has fostered interest since early androgen studies in the 1940s. Little knowledge has surfaced about the role mutations play in prostate cancer development. A group at the Michigan Center for Translation Pathology studied exomes of lethal, metastatic CRPC and documented the overall mutation rates. In classifying these mutations, the monoclonal cause of CRPC was recognized. Nine identified genes showed significant mutations. Six of these genes had previously been reported as mutated in prostate cancer. The analysis also found significantly mutated androgen receptor (AR) cofactors and linked proteins, including FOXA1 and MLL2. Another finding concerned an aberration in CHD1. Prostate cancers with deletions or mutations in CHD1 showed a strong correlation with ETS gene family fusion negative prostate cancers (96%). In profiling these exomes, this group provides an original method to identify deletions and mutations that drive CRPC progression.
Related JoVE Video
Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-15-2013
Show Abstract
Hide Abstract
Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently.
Related JoVE Video
Monitor tumor burden with circulating tumor DNA.
Cancer Biol. Ther.
PUBLISHED: 06-13-2013
Show Abstract
Hide Abstract
There is a need to identify better biomarkers to monitor diseases and/or assess therapeutic responses. For those with cancer, one can identify DNA fragments that contain somatic mutations originating in the tumor DNA in plasma or serum. There have been several early studies suggesting that advances in sequencing technologies will allow identification of somatic genomic alterations that can be used to monitor tumor dynamics. Dawson et.al. investigated circulating cell-free DNA carrying tumor specific alterations in patients with breast cancer. The authors compared CT imaging from 30 women with metastatic breast cancer receiving treatment, using two assays for circulating tumor DNA, CA 15-3, and CTCs. Taken the two methods together circulating tumor DNA was detected in 29 or 30 women (97%) and 115 of 141 plasma samples (82%). Circulating tumor DNA levels showed a greater dynamic range and greater correlation with changes in tumor burden than did CA 15-3 or CTC. The relatively small study showed that circulating tumor DNA has a superior sensitivity to other circulating biomarkers and a dynamic range that correlates with tumor burden.
Related JoVE Video
Phase I trial of a new schedule of romidepsin in patients with advanced cancers.
Clin. Cancer Res.
PUBLISHED: 06-11-2013
Show Abstract
Hide Abstract
Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers.
Related JoVE Video
Electrocardiographic studies of romidepsin demonstrate its safety and identify a potential role for K(ATP) channel.
Clin. Cancer Res.
PUBLISHED: 04-15-2013
Show Abstract
Hide Abstract
Romidepsin is a histone deacetylase inhibitor (HDI) approved for the treatment of both cutaneous and peripheral T-cell lymphoma (CTCL and PTCL). During development, a thorough assessment of cardiac toxicity was conducted.
Related JoVE Video
Phase II study of satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer: a pharmacogenetic assessment of outcome and toxicity.
Clin Genitourin Cancer
PUBLISHED: 04-02-2013
Show Abstract
Hide Abstract
We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy.
Related JoVE Video
Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 03-05-2013
Show Abstract
Hide Abstract
Glypican-3 (GPC3) has emerged as a candidate therapeutic target in hepatocellular carcinoma (HCC), but the oncogenic role of GPC3 in HCC is poorly understood. Here, we report a human heavy-chain variable domain antibody, HN3, with high affinity (Kd = 0.6 nM) for cell-surface-associated GPC3 molecules. The human antibody recognized a conformational epitope that requires both the amino and carboxy terminal domains of GPC3. HN3 inhibited proliferation of GPC3-positive cells and exhibited significant inhibition of HCC xenograft tumor growth in nude mice. The underlying mechanism of HN3 action may involve cell-cycle arrest at G1 phase through Yes-associated protein signaling. This study suggests a previously unrecognized mechanism for GPC3-targeted cancer therapy.
Related JoVE Video
Phase II trial of bevacizumab and satraplatin in docetaxel-pretreated metastatic castrate-resistant prostate cancer.
Urol. Oncol.
PUBLISHED: 02-21-2013
Show Abstract
Hide Abstract
Satraplatin is an oral platinum compound that has demonstrated efficacy and tolerability in prostate cancer. Preclinical synergy between bevacizumab and platinum has been noted.
Related JoVE Video
Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer.
BJU Int.
PUBLISHED: 02-18-2013
Show Abstract
Hide Abstract
To assess the efficacy and toxicity of cediranib, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel-based therapy.
Related JoVE Video
Pharmacokinetics of intravenous voriconazole in obese patients: implications of CYP2C19 homozygous poor metabolizer genotype.
Pharmacotherapy
PUBLISHED: 02-11-2013
Show Abstract
Hide Abstract
There is a paucity of pharmacokinetic studies describing weight-based dosing of intravenous voriconazole in obese patients. In this case report, we describe the pharmacokinetics of intravenous voriconazole in an obese CYP2C19 homozygous poor metabolizer and review previously reported data regarding the use of intravenous voriconazole in obese patients. A 17-year-old obese Hispanic male patient (body mass index 35 kg/m(2) ) received intravenous voriconazole for the treatment of suspected aspergillosis. After 2.5 days of voriconazole 4 mg/kg intravenously every 12 hours based on adjusted body weight, the voriconazole area under the serum concentration-time curve over the course of a single (12-hr) dosing interval and trough concentration were 86,100 ng · hr/ml and 6.2 µg/ml, respectively. Six days later, the voriconazole dosage was decreased. A trough concentration measured just before the dosage reduction (after 8.5 days of voriconazole 4 mg/kg intravenously every 12 hours based on adjusted body weight) remained elevated at 5.8 µg/ml. Genotyping revealed a CYP2C19 homozygous poor metabolizer (CYP2C19*2/*2). Voriconazole was subsequently discontinued due to QTc prolongation. These data and those from two recent publications suggest that voriconazole does not distribute extensively into human adipose tissue and that obese patients should be dosed on an adjusted body weight basis. If an obese patient dosed on total body weight is also a CYP2C19 poor metabolizer, serum voriconazole concentrations will be further elevated, potentially leading to drug-induced toxicity.
Related JoVE Video
Insulin-like growth factors and insulin-like growth factor-binding proteins and prostate cancer risk: results from the prostate cancer prevention trial.
Cancer Prev Res (Phila)
PUBLISHED: 01-11-2013
Show Abstract
Hide Abstract
The role of the insulin-like growth factor (IGF) axis and whether IGFs interact with androgen-suppressing agents in relation to prostate carcinogenesis is unclear. This nested case-control study (n = 1,652 cases/1,543 controls) examined whether serum IGF1, IGF2, IGFBP2, IGFBP3, and the IGF1:IGFBP3 ratio were associated with prostate cancer in the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Baseline serum was assayed for IGF-axis analytes using ELISA. Logistic regression estimated ORs and 95% confidence intervals for risk of total, low-grade (Gleason 2-6) and high-grade (Gleason 7-10) cancers. Results were stratified by intervention assignment. In both the placebo and finasteride arms, serum IGF1, IGF2, IGFBP3, and the IGF1:IGFBP3 ratio were not associated with prostate cancer. However, men in the highest versus lowest quartile of serum IGFBP2 had a 48% (P(trend) = 0.02) and 55% (P(trend) = 0.01) increased risk for total and low-grade cancers, respectively. These IGFBP2 associations were attenuated and no longer statistically significant in the finasteride arm. Our results suggest that in general, serum IGF-axis analytes were not associated with prostate cancer risk in the PCPT in which presence or absence of all cancers was biopsy-determined. The exception was the finding that high serum IGFBP2 is a risk factor for low-grade disease, which was attenuated for men on finasteride. Further research is needed to understand better the risk incurred by high IGFBP2 and whether androgen-suppressing agents such as finasteride influence aspects of IGFBP2 physiology relevant to prostate carcinogenesis.
Related JoVE Video
A rapid ultra HPLC-MS/MS method for the quantitation and pharmacokinetic analysis of 3-deazaneplanocin A in mice.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 01-02-2013
Show Abstract
Hide Abstract
3-Deazaneplanocin A (DZNep) has been shown to have anti-cancer activity in numerous cancer types and its continued preclinical, and eventual clinical, drug development will require rapid and sensitive bioanalytical methods in order to quantitate this drug for pharmacokinetic analyses. The ultra HPLC with positive thermospray tandem mass spectrometric (LC-MS/MS) detection affords the most sensitive (limit of quantitation 5ng/mL) and rapid (3min run time) bioanalytical method to date for DZNep. Due to the polar nature of this drug and the internal standard (tubercidin), a hydrophilic-interaction column (HILIC) was used. The method was accurate, with less than 10% deviation from nominal values, as well as precise, where both within-day and between-day precisions were less than 15%. A liquid-liquid extraction procedure was able to recover ?90% of drug from a small volume (50?L) of mouse plasma. This method was successfully applied to a pharmacokinetic study in mice intravenously injected with DZNep.
Related JoVE Video
Are race-specific ERCC1 haplotypes in melanoma cases versus controls related to the predictive and prognostic value of ERCC1 N118N?
BMJ Open
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
Although it does not alter the ERCC1 phenotype, the ERCC1 500C>T (rs11615) polymorphism has undergone a myriad of investigations into its role as a marker for nucleotide excision repair (NER) function in different races, diseases and treatment outcomes. The goal of our study was to test the hypothesis that 500C>T is in linkage disequilibrium (LD) with causative alleles, and that these haplotypes are more frequent in Caucasians with melanoma than in healthy Caucasians or African Americans.
Related JoVE Video
A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas.
Clin. Cancer Res.
PUBLISHED: 09-09-2011
Show Abstract
Hide Abstract
To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas.
Related JoVE Video
Phase I trial of 7-hydroxystaurosporine and fludararbine phosphate: in vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia.
Leuk. Lymphoma
PUBLISHED: 07-12-2011
Show Abstract
Hide Abstract
This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.
Related JoVE Video
Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1? in advanced solid tumors.
Clin. Cancer Res.
PUBLISHED: 06-14-2011
Show Abstract
Hide Abstract
Hypoxia-inducible factor 1 (HIF-1) ? is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1? expression in preclinical models. We designed a pilot trial to measure HIF-1? inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1?, after treatment with oral topotecan.
Related JoVE Video
SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer.
J. Clin. Oncol.
PUBLISHED: 05-23-2011
Show Abstract
Hide Abstract
Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT.
Related JoVE Video
A sensitive and rapid ultra HPLC-MS/MS method for the simultaneous detection of clopidogrel and its derivatized active thiol metabolite in human plasma.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 04-13-2011
Show Abstract
Hide Abstract
A sensitive, selective, and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (uHPLC-MS/MS) was developed for the simultaneous quantification of clopidogrel (Plavix(®)) and its derivatized active metabolite (CAMD) in human plasma. Derivatization of the active metabolite in blood with 2-bromo-3-methoxy acetophenone (MPB) immediately after collection ensured metabolite stability during sample handling and storage. Following addition of ticlopidine as an internal standard and simple protein precipitation, the analytes were separated on a Waters Acquity UPLC™ sub-2 ?m-C(18) column via gradient elution before detection on a triple-quadrupole MS with multiple-reaction-monitoring via electrospray ionization. The method was validated across the clinically relevant concentration range of 0.01-50 ng/mL for parent clopidogrel and 0.1-150 ng/mL (r(2)=0.99) for CAMD, with a fast run time of 1.5 min to support pharmacokinetic studies using 75, 150, or 300 mg oral doses of clopidogrel. The analytical method measured concentrations of clopidogrel and CAMD with accuracy (%DEV) <±12% and precision (%CV) of <±6%. The method was successfully applied to measure the plasma concentrations of clopidogrel and CAMD in three subjects administered single oral doses of 75, 150, and 300 mg clopidogrel. It was further demonstrated that the derivatizing agent (MPB) does not affect clopidogrel levels, thus from one aliquot of blood drawn clinically, this method can simultaneously quantify both clopidogrel and CAMD with sensitivity in the picogram per mL range.
Related JoVE Video
Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms.
Clin. Cancer Res.
PUBLISHED: 03-29-2011
Show Abstract
Hide Abstract
A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma).
Related JoVE Video
CHIP and gp78-mediated ubiquitination of CYP3A4: Implications for the pharmacology of anticancer agents.
Cancer Biol. Ther.
PUBLISHED: 03-15-2011
Show Abstract
Hide Abstract
The autocrine motility factor receptor or glycoprotein-78 (gp78) and C-terminus of Hsp70-interacting protein (CHIP) are E3-ligases required for ubiquitination of cytochrome P450s of the 3A subfamily (CYP3A) in endoplasmic reticulum-associated degradation (ERAD). The CYP isozyme 3A4 (CYP3A4) is responsible for the metabolism of the majority of xenobiotics including anticancer agents. Much variability in clinical response to chemotherapy is observed and it has been suggested that variability in CYP3A4 expression could be a factor. The study reviewed in this journal club comments on the importance of further characterizing gp78 and CHIP as relevant proteins in ERAD of CYP3A4. This study demonstrated how both gp78 and CHIP play direct roles in reducing CYP3A4 protein content as well as CYP3A4 ubiquitination. Interestingly, when gp78 and CHIP were knocked down by siRNAs directed towards each protein, the stabilized CYP3A4 remained functional. This has implications for drug-drug interactions for agents metabolized by CYP3A4, which can influence drug exposure levels. This is relevant because most anticancer agents have very narrow therapeutic windows, thus even slight changes in CYP3A4 levels could alter the exposure of that drug and result in either insufficient efficacy or toxicity. Future studies must explore genetic variability in the ERAD pathway and identify new factors that influence CYP3A ERAD in order to better characterize how CYP3A variability affects anticancer drug pharmacology.
Related JoVE Video
Population pharmacokinetic analysis of sorafenib in patients with solid tumours.
Br J Clin Pharmacol
PUBLISHED: 03-12-2011
Show Abstract
Hide Abstract
Sorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFR? and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The pharmacokinetics (PK) of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC).
Related JoVE Video
Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques.
Blood
PUBLISHED: 03-08-2011
Show Abstract
Hide Abstract
IL-15 uses the heterotrimeric receptor IL-2/IL-15R? and the ? chain shared with IL-2 and the cytokine-specific IL-15R?. Although IL-15 shares actions with IL-2 that include activation of natural killer (NK) and CD8 T cells, IL-15 is not associated with capillary leak syndrome, activation-induced cell death, or with a major effect on the number of functional regulatory T cells. To prepare for human trials to determine whether IL-15 is superior to IL-2 in cancer therapy, recombinant human IL-15 (rhIL-15) was produced under current good manufacturing practices. A safety study in rhesus macaques was performed in 4 groups of 6 animals each that received vehicle diluent control or rhIL-15 at 10, 20, or 50 ?g/kg/d IV for 12 days. The major toxicity was grade 3/4 transient neutropenia. Bone marrow examinations demonstrated increased marrow cellularity, including cells of the neutrophil series. Furthermore, neutrophils were observed in sinusoids of enlarged livers and spleens, suggesting that IL-15 mediated neutrophil redistribution from the circulation to tissues. The observation that IL-15 administration was associated with increased numbers of circulating NK and CD8 central and effector-memory T cells, in conjunction with efficacy studies in murine tumor models, supports the use of multiple daily infusions of rhIL-15 in patients with metastatic malignancies.
Related JoVE Video
Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma.
Blood
PUBLISHED: 02-25-2011
Show Abstract
Hide Abstract
Romidepsin (depsipeptide or FK228) is a histone deacetylase inhibitor, one of a new class of agents active in T-cell lymphoma. A phase 2 trial was conducted in cutaneous (CTCL) and peripheral (PTCL) T-cell lymphoma. Major and durable responses in CTCL supported the approval of romidepsin for CTCL. Forty-seven patients with PTCL of various subtypes including PTCL NOS, angioimmunoblastic, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma were enrolled. All patients had received prior therapy with a median of 3 previous treatments (range 1-11); 18 (38%) had undergone stem-cell transplant. All patients were evaluated for toxicity; 2 patients discovered to be ineligible were excluded from response assessment. Common toxicities were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. Complete responses were observed in 8 and partial responses in 9 of 45 patients, for an overall response rate of 38% (95% confidence interval 24%-53%). The median duration of overall response was 8.9 months (range 2-74). Responses were observed in various subtypes, with 6 responses among the 18 patients with prior stem-cell transplant. The histone deacetylase inhibitor romidepsin has single agent clinical activity associated with durable responses in patients with relapsed PTCL.
Related JoVE Video
Expression of OATP family members in hormone-related cancers: potential markers of progression.
PLoS ONE
PUBLISHED: 01-20-2011
Show Abstract
Hide Abstract
The organic anion transporting polypeptide (OATP) family of transporters has been implicated in prostate cancer disease progression probably by transporting hormones or drugs. In this study, we aimed to elucidate the expression, frequency, and relevance of OATPs as a biomarker in hormone-dependent cancers. We completed a study examining SLCO1B3, SLCO1B1 and SLCO2B1 mRNA expression in 381 primary, independent patient samples representing 21 cancers and normal tissues. From a separate cohort, protein expression of OATP1B3 was examined in prostate, colon, and bladder tissue. Based on expression frequency, SLCO2B1 was lower in liver cancer (P?=?0.04) which also trended lower with decreasing differentiation (P?=?0.004) and lower magnitude in pancreatic cancer (P?=?0.05). SLCO2B1 also had a higher frequency in thyroid cancer (67%) than normal (0%) and expression increased with stage (P?=?0.04). SLCO1B3 was expressed in 52% of cancerous prostate samples and increased SLCO1B3 expression trended with higher Gleason score (P?=?0.03). SLCO1B3 expression was also higher in testicular cancer (P?=?0.02). SLCO1B1 expression was lower in liver cancer (P?=?0.04) which trended lower with liver cancer grade (P?=?0.0004) and higher with colon cancer grade (P?=?0.05). Protein expression of OATP1B3 was examined in normal and cancerous prostate, colon, and bladder tissue samples from an independent cohort. The results were similar to the transcription data, but showed distinct localization. OATPs correlate to differentiation in certain hormone-dependent cancers, thus may be useful as biomarkers for assessing clinical treatment and stage of disease.
Related JoVE Video
Serum estrogen levels and prostate cancer risk in the prostate cancer prevention trial: a nested case-control study.
Cancer Causes Control
PUBLISHED: 01-17-2011
Show Abstract
Hide Abstract
Finasteride reduces prostate cancer risk by blocking the conversion of testosterone to dihydrotestosterone. However, whether finasteride affects estrogens levels or change in estrogens affects prostate cancer risk is unknown.
Related JoVE Video
The ERCC1 N118N polymorphism does not change cellular ERCC1 protein expression or platinum sensitivity.
Mutat. Res.
PUBLISHED: 01-10-2011
Show Abstract
Hide Abstract
Genetic polymorphisms in ERCC1 are thought to contribute to altered sensitivity to platinum-based chemotherapy. Although ERCC1 N118N (500 C>T, rs11615) is the most studied polymorphism, the impact of this polymorphism on platinum-based chemotherapy remains unclear. This is the first study in which the functional impact of ERCC1 N118N on gene expression and platinum sensitivity was explored. The aim of this study is to investigate if the reduced codon usage frequency of AAT, which contains the variant allele of the silent mutation, has functional impact on ERCC1 in a well-controlled biological system. Specifically, the ERCC1 cDNA clone with either the C or T allele was introduced into an ERCC1 deficient cell line, UV20, and assayed for the effect of the two alleles on ERCC1 transcription, translation and platinum sensitivity. Both ERCC1 mRNA and protein expression levels increased upon cisplatin treatment, peaking at 4h post-treatment, however there were no differences between the two alleles (p>0.05). Cells complemented with ERCC1 showed significantly higher survival proportion than the parental cell line following platinum exposure (p<0.0001), although no differences were observed between the cells transfected with the wild type or the polymorphic allele. These data suggest that N118N itself is not related to the phenotypic differences in ERCC1 expression or function, but rather this polymorphism may be linked to other causative variants or haplotypes.
Related JoVE Video
Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers.
PLoS ONE
PUBLISHED: 01-10-2011
Show Abstract
Hide Abstract
Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion.
Related JoVE Video
Transition of a clinical trial into translational research: the prostate cancer prevention trial experience.
Cancer Prev Res (Phila)
PUBLISHED: 12-15-2010
Show Abstract
Hide Abstract
Large clinical trials provide a tremendous opportunity to integrate correlative, comprehensive biological studies with invaluable repositories of biospecimens and clinical and other data from the trial. The Prostate Cancer Prevention Trial (PCPT) was a phase III randomized, double-blind, placebo-controlled clinical trial of finasteride in 18,882 men. Clinical data and blood and tissue specimens were collected at baseline and throughout the study, offering an opportunity to create a program project to investigate hypotheses related to the biology underlying the PCPT findings as well as the etiology and risk of prostate cancer. The transition of the randomized PCPT into this translational and epidemiologic scientific investigation required extensive planning and coordination. Five individual but interrelated projects were brought together with the underlying program theme of the genetic, metabolic, and environmental factors associated with the risks of overall and high-grade prostate cancer and how these factors affected the efficacy of finasteride in preventing cancer. All projects with serum-based measures use a single, shared, nested case-control sample of participants so that each subject provides a more complete biomarker and genetic profile for the evaluation of joint effects of these factors. Strengths of this program include the following: 1) the control group contains only men who are negative for biopsy-detected cancer, 2) the statistical methods to evaluate associations of risk factors with disease are shared across all projects, 3) the large number of cancer cases with fully characterized genetic, metabolic, and behavioral exposures, 4) a central pathology core histopathologically classified the prostate cancer, and 5) cancer cases identified during the PCPT reflect the characteristics of cases currently being detected in the prostate-specific antigen screening era, leading to contemporary and highly relevant results. This article describes the comprehensive methodology and multidisciplinary collaborations, both national and international, essential to a major risk-modeling research program. We provide a framework for doing collaborative research in an international setting structured around a common theme of a clinical trial.
Related JoVE Video
Cabazitaxel: filling one of the gaps in the treatment of prostate cancer.
Cancer Biol. Ther.
PUBLISHED: 12-15-2010
Show Abstract
Hide Abstract
Prostate cancer is the second most frequently diagnosed cancer in men and the fifth most common cancer overall. Globally, more than 900,000 new cases of prostate cancer will be diagnosed in 2010 and more than 260,000 will, unfortunately, die from the disease. In the US, an estimated 217,000 new cases of prostate cancer and 32,000 deaths are expected this year. Definitive therapy (surgery or radiation) is highly effective, but if the tumor escapes the gland, treatment options are limited. For this population of patients, androgen suppression is the cornerstone of initial therapy. Furthermore, progression to castration resistant prostate cancer (CRPC) is inevitable. The current front-line treatment for patients with CRPC is the chemotherapeutic agent docetaxel (administered every 3 weeks). Until now, it is the only agent that has been shown to prolong survival in CRPC. The approval trial for docetaxel found a median overall survival of 19.2 months for patients receiving docetaxel plus prednisone compared to 16.3 months for patients receiving mitoxantrone plus prednisone (p=0.0094). Mitoxantrone plus prednisone is often utilized for its palliative benefits, but two randomized trials failed to demonstrate a survival advantage.
Related JoVE Video
Prostate cancer genomic signature offers prognostic value.
Cancer Biol. Ther.
PUBLISHED: 12-01-2010
Show Abstract
Hide Abstract
Previous attempts to link prostate cancer progression to genetic alterations have been unsuccessful, and consequently, there is still no reliable predictor of prognosis for men with this disease. A recent study by Taylor et al., published in Cancer Cell, assesses copy number alterations, mutations, and transcriptomes in 218 tumors and 12 prostate cancer cell lines and xenografts. Their analysis identifies frequencies of ERG alterations, 8p loss and 8q gain similar to previous findings. It also reveals novel genetic factors in prostate cancer progression, including the androgen receptor coactivator, NCOA2, which serves as an oncogene in about 11% of tumors, and a deletion at chromosome 3p14, which was associated with TMPRSS-ERG fusion. The copy number alteration data demonstrates six distinct subgroups of prostate cancer with considerable variation in time to biochemical relapse. Classification of prostate cancer into these genetic subgroups may help clinicians predict the likelihood of disease progression in newly diagnosed men, ultimately guiding treatment decisions and therapy development.
Related JoVE Video
Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy.
Clin. Cancer Res.
PUBLISHED: 11-24-2010
Show Abstract
Hide Abstract
In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC).
Related JoVE Video
Impact of ABCB1 allelic variants on QTc interval prolongation.
Clin. Cancer Res.
PUBLISHED: 11-24-2010
Show Abstract
Hide Abstract
Although the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e., blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT prolongation and cardiotoxicity.
Related JoVE Video
Estrogen receptor ? and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with castration-resistant prostate cancer treated with docetaxel-based therapy.
J. Clin. Endocrinol. Metab.
PUBLISHED: 11-24-2010
Show Abstract
Hide Abstract
Reactive estrogen species cause genotoxicity and interfere with docetaxel-mediated tubulin polymerization resulting in shortened survival in men with castrate-resistant prostate cancer (CRPC).
Related JoVE Video
A SNP in CYP2C8 is not associated with the development of bisphosphonate-related osteonecrosis of the jaw in men with castrate-resistant prostate cancer.
Ther Clin Risk Manag
PUBLISHED: 11-19-2010
Show Abstract
Hide Abstract
A single nucleotide polymorphism (SNP) in CYP2C8 (rs1934951), was previously identified in a genome-wide association study as a risk factor for the development of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BPs) for multiple myeloma. To determine if the same SNP is also associated with the development of ONJ in men receiving BPs for bone metastases from prostate cancer, we genotyped 100 men with castrate-resistant prostate cancer treated with bisphosphonates for bone metastases, 17 of whom developed ONJ. Important clinical characteristics, including type and duration of bisphosphonate therapy, were consistent among those who developed ONJ and those who did not. We found no significant correlation between the variant allele and the development of ONJ (OR = 0.63, 95% CI: 0.165-2.42, P > 0.47). This intronic SNP in CYP2C8 (rs1934951) does not seem to be a risk factor for the development of bisphosphonate-related ONJ in men with prostate cancer. It is important to note that this is only the second study to investigate the genetics associated with BP-related ONJ and the first to do so in men with prostate cancer. More studies are needed to identify genetic risk factors that may predict the development of this important clinical condition.
Related JoVE Video
A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer.
Clin. Cancer Res.
PUBLISHED: 11-16-2010
Show Abstract
Hide Abstract
P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to show meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third-generation, potent, noncompetitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel.
Related JoVE Video
Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.
Ann Pharmacother
PUBLISHED: 10-19-2010
Show Abstract
Hide Abstract
Several microtubule targeting agents are capable of inducing CYP3A4 via activation of the pregnane X receptor (PXR; NR1I2).
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.