Abiraterone acetate is an orally administered potent inhibitor of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1 or CYPc17), which is essential for synthesis of testosterone from cholesterol. While decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer, residual androgens may still be detected in patients treated with LHRH agonists. Treatment with abiraterone results in rapid, and complete, inhibition of androgen synthesis in the adrenal glands and within the tumor itself. An overall survival benefit of maximal androgen suppression was recently demonstrated in a randomized placebo controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate resistant prostate cancer previously treated with docetaxel chemotherapy. Abiraterone’s efficacy demonstrates the importance of androgen signaling in patients with castrate resistant metastastic disease, and the importance of studies of other novel agents such as MDV3100, an androgen receptor inhibitor, that additionally targets androgen receptor translocation. These promising results now pose a new angle to an old problem regarding hormonal therapy and raise new questions about how resistance develops, how to best sequence therapy, and how to optimize combinations with other emerging novel targeted agents.
Abiraterone; Prostate Cancer; CYP17A1; CYP17; CYPc17
R-(-)-gossypol acetic acid (AT-101), a natural BH3 mimetic, is investigated in a Phase I/II clinical trial for the treatment of advanced solid tumor malignancies. Gossypol undergoes rapid degradation in solution phase, which causes major technical difficulty for its quantitation in plasma. We developed and validated a sensitive HPLC assay for pharmacokinetic evaluation of gossypol. Acetonitrile deproteinization method was chosen for sample preparation and Schiff's base derivative, R-(-)-gossypol-diamino-propanol (GDP), was used as internal standard. Chromatographic separation of gossypol in plasma was performed using a Zorbax Eclipse XDB column C18 at 30°C. The mobile phase consists of 10 mmol/L KH2PO4 (pH=3.0) and acetonitrile (20:80) at 1.0 mL/min flow rate. Linearity ranged over 56-3585 ng/mL (R2=0.9997±0.0003, n=4), and the limit of detection was 28 ng/mL. The intra- and inter-assay precision was less than 13.7% and the bias ranged from -7.4 to 7.0%. The method was successfully applied to characterize the pharmacokinetics of AT-101 in a Phase I clinical trial. The validated assay is accurate, and sensitive with minimum loss and rapid analysis time and suitable for quantification of gossypol for pharmacokinetics evaluation.
R-(-)-gossypol; HPLC-UV; pharmacokinetics
ADHD, sleep, and ADHD treatments are highly interrelated. In this review, we describe the effects of stimulants and non stimulant medications on sleep in children, adolescents, and adults with ADHD. Clinical predictors of sleep problems during pharmacotherapy include age, sleep problems prior to initiating treatment, and dose and dosing schedule. As yet, we have little understanding of the biological or genetic factors related to individual variation in drug response and sleep.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0130-0) contains supplementary material, which is available to authorized users.
ADHD; Sleep; Psychopharmacology
Despite controversy over the benefit of prostate specific antigen (PSA) screening, little is known about risk profiles and treatment patterns in men diagnosed with prostate cancer who have a PSA value less than or equal to 4 ng/mL.
We utilized data from the Surveillance, Epidemiology, End Results system to describe patient characteristics and treatment patterns of 123,934 men with newly diagnosed prostate cancer in 2004–2006. Age-standardized treatment rates were calculated in five-year age strata. Logistic regression was used to quantify the odds ratios (OR) of men with low– and high–risk disease and the use of radical prostatectomy (RP) or radiation therapy (RT).
Men with a PSA of 4.0 ng/ml or less represent 14% of incident prostate cancer cases. Fifty-four percent of men diagnosed with prostate cancer and PSA ≤ 4.0 ng/mL harbor low-risk disease (stage ≤ T2a, PSA level ≤ 10 ng/mL, and Gleason score ≤ 6), but over 75% of them received RP or RT. Men with screen-detected prostate cancer and PSA values ≤ 4 ng/mL were 1.49 (CI 1.38–1.62) and 1.39 (CI 1.30–1.49) times more likely to receive RP and RT, respectively, and were less likely to have high-grade disease than men who had non-screen detected prostate cancer (OR=0.67; 95% CI:0.60–0.76).
Most men diagnosed with prostate cancer with a PSA threshold ≤ 4.0 ng/mL had low-risk disease but underwent aggressive local therapy. Lowering biopsy threshold, while lacking the ability to distinguish indolent cancers from aggressive cancers, may increase overdiagnosis and overtreatment.
Normal brain development is highly dependent on adequate levels of iodine and thyroid hormone. It has been suggested that Attention Deficit Hyperactivity Disorder (ADHD) is the consequence of prenatal thyroidal endocrine disruption. The hypothesis was examined using neonatal thyroxine levels as a bio-marker of prenatal thyroid status and comparing it to subsequent development of ADHD.
Design and methods
In a matched case-control study, cases were defined as children diagnosed with ADHD, while children born in the same hospital and tested on the same day served as matched controls. Conditional logistic regression analysis with unequal numbers of controls was performed.
The neonatal thyroxine levels were within normal limits for each of the children who were subsequently diagnosed as having ADHD, and their distribution was no different from that of their controls.
Children diagnosed with ADHD do not demonstrate prenatal thyroidal dysfunction as reflected in the newborn thyroxine levels, therefore neonatal thyroxine levels are not a bio-marker for the subsequent development of ADHD.
Neonatal thyroxine (T4); Thyroid hormone; Attention deficit hyperactivity disorder; ADHD; Thyroid dysfunction
Dubowitz Syndrome is an autosomal recessive disorder with a unique set of clinical features including microcephaly and susceptibility to tumor formation. Although more than 140 cases of Dubowitz syndrome have been reported since 1965, the genetic defects of this disease has not been identified. In this study, we systematically analyzed the DNA damage response and repair capability of fibroblasts established from a Dubowitz Syndrome patient. Dubowitz syndrome fibroblasts are hypersensitive to ionizing radiation, bleomycin, and doxorubicin. However, they have relatively normal sensitivities to mitomycin-C, cisplatin, and camptothecin. Dubowitz syndrome fibroblasts also have normal DNA damage signaling and cell cycle checkpoint activations after DNA damage. These data implicate a defect in repair of DNA double strand break (DSB) likely due to defective non-homologous end joining (NHEJ). We further sequenced several genes involved in NHEJ, and identified a pair of novel compound mutations in the DNA Ligase IV gene. Furthermore, expression of wild type DNA ligase IV completely complement the DNA repair defects in Dubowitz syndrome fibroblasts, suggesting that the DNA ligase IV mutation is solely responsible for the DNA repair defects. These data suggests that at least subset of Dubowitz syndrome can be attributed to DNA ligase IV mutations.
Activation of the epidermal growth factor pathway is important in prostate cancer development and the transcription of androgen receptor regulated genes. This study evaluated the potential activity of lapatinib in men with biochemically-relapsed androgen-dependent (stage D0) prostate cancer.
Patients with a rising PSA after primary therapy for prostate cancer were enrolled. A PSA doubling time (PSADT) <12 months was required. Lapatinib was administered at 1,500 mg orally daily. Outcome measures were changes in PSA kinetics. Primary tumor blocks were obtained and assessed for EGFR expression, EGFR Q787Q polymorphism, and Kras 38 mutational status.
49 patients were enrolled (14 ineligible), resulting in 35 pts for analysis. No PSA response was observed; best response was stable disease (n=28, 80.0%). Pre-treatment average slope was 0.19 log (PSA)/month (PSADT=3.70 months), in contrast to on-treatment average slope of 0.13 log (PSA)/month (PSADT=5.44 months) using linear mixed effects models (p=0.006). Median progression-free survival (PFS) was 17.4 months for the high EGFR group and 6.0 months for the low EGFR group (p=0.50). Patients with Kras 38 mutation had shorter PFS than those without Kras 38 mutation (p=0.09).
Although no PSA responses (primary endpoint) was observed, lapatinib may have biologic activity in men with stage D0 prostate cancer as evidenced by a decrease in PSA slope in this non-randomized study. Additional trials assessing the role of EGFR overexpression and Kras wild type status in prostate cancer should be investigated.
Epidermal growth factor receptor; tyrosine kinase inhibitors; clinical trial
Integrins are involved in prostate cancer metastasis by regulating cell adhesion, migration, invasion, motility, angiogenesis and bone metabolism. We evaluated the efficacy of two dose levels of cilengitide in patients (pts) with castrate resistant prostate cancer (CRPC).
Chemotherapy-naïve, asymptomatic metastatic CRPC pts were randomized to cilengitide 500mg or 2000mg IV twice weekly using parallel 2-stage design. The primary endpoint was rate of objective clinical progression at six-months. Secondary endpoints included clinical and PSA response rates, safety and effects of cilengitide treatment on circulating tumor cells (CTCs) and bone remodeling markers.
Forty-four pts were accrued to first stage (22/arm). Median number of cycles was three in both arms (500mg arm: 1–8; 2000 mg arm: 1–15). At six months, two pts (9%) on the 500mg arm and five pts (23%) on the 2000mg arm had not progressed. Best objective response was stable disease (SD) in seven pts for 9.9[8.1,20.9] months. There were three grade 3 and no grade 4 toxicities. At 12 weeks, analysis of bone markers did not reveal significant trends. At progression, bone specific alkaline phosphatase and N-telopeptide increased in all pts, less so in pts on the 2000mg arm and in pts on both arms who obtained SD at 6 months. CTCs increased over time in both arms.
Cilengitide was well tolerated with modest clinical effect in favor of the higher dose. The unique trial design including a shift from response rate to objective progression as the endpoint, and not acting on PSA increases was feasible.
prostate cancer; metastatic disease; integrins; angiogenesis; cilengitide; bone biomarkers
To compare the dose effects of long-acting extended-release dexmethylphenidate (ER d-MPH) and ER mixed amphetamine salts (ER MAS) on attention-deficit/hyperactivity disorder (ADHD) symptom dimensions, global and specific impairments, and common adverse events associated with stimulants.
Fifty-six children and adolescents with ADHD participated in an 8-week, double-blind, crossover study comparing ER d-MPH (10, 20, 25–30 mg) and ER MAS (10, 20, 25–30) with a week of randomized placebo within each drug period. Efficacy was assessed with the ADHD Rating Scale-IV (ADHD-RS-IV), whereas global and specific domains of impairment were assessed with the Clinical Global Impressions Severity and Improvement Scales and the parent-completed Weiss Functional Impairment Scale, respectively. Insomnia and decreased appetite, common stimulant-related adverse events, were measured with the parent-completed Stimulant Side Effects Rating Scale.
Both ER d-MPH and ER MAS were associated with significant reductions in ADHD symptoms. Improvement in Total ADHD and Hyperactivity/Impulsivity symptoms were strongly associated with increasing dose, whereas improvements in Inattentive symptoms were only moderately associated with dose. About 80% demonstrated reliable change on ADHD-RS-IV at the highest dose level of ER MAS compared with 79% when receiving ER d-MPH. Decreased appetite and insomnia were more common at higher dose levels for both stimulants. Approximately 43% of the responders were preferential responders to only one of the stimulant formulations.
Dose level, rather than stimulant class, was strongly related to medication response.
Due to significant individual variability in Attention Deficit/Hyperactivity Disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examines the role of 4 catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response.
89 stimulant-naïve children with ADHD aged 7–11 participated in a randomized, double-blind, crossover trial of long-acting MPH. Parents and teachers assessed each child’s response on placebo and three MPH dosage levels using the Vanderbilt ADHD rating scales. Children were genotyped for polymorphisms in the dopamine transporter’s (DAT) 3’ untranslated region, dopamine receptor D4‘s (DRD4) exon 3, catechol-O-methyltransferase’s (COMT) codon 158, and adrenergic α2A-receptor’s (ADRA2A) promoter. Linear mixed models evaluated gene, dose (mg/kg/day), and gene*dose effects on inattentive and hyperactive-impulsive domain outcomes.
The most statistically significant gene*dose interactions were observed on hyperactive-impulsive symptoms for DRD4 and DAT polymorphisms, with participants lacking the DAT 10-repeat allele experiencing greater improvements in symptoms with increasing dose compared to 10-repeat carriers (p=0.008), and those lacking the DRD4 4-repeat allele showing less improvement across MPH doses compared to 4-repeat carriers (p=0.02).
This study suggests that DAT and DRD4 polymorphisms may be associated with individual variability in methylphenidate dose-response, although further research in larger samples is required to confirm these findings and their clinical utility.
ADHD; pharmacogenetics; methylphenidate; dopamine receptor D4; dopamine transporter
In the preclinical setting, phosphorylation and subsequent proteosomal degradation of the proapoptotic protein BIM confers resistance to paclitaxel in solid tumors with RAS/RAF/MAPK pathway activation. Concurrent administration of the proteasome inhibitor bortezomib enables paclitaxel-induced BIM accumulation, restoring cancer cell apoptosis in vitro and producing tumor regression in mice in vivo. A Phase I study was conducted to determine the MTD of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors commonly exhibiting MAPK pathway activation were treated with weekly paclitaxel and bortezomib. Starting doses were 40 mg/m2 for paclitaxel and 0.7 mg/m2 for bortezomib. A modified continual reassessment method (MCRM) adapted for 2-drug escalation was used for MTD determination with 3-patient cohorts treated at each dose level. MTD was reached at 60 mg/m2 paclitaxel and 1.0 mg/m2 bortezomib, the recommended phase II dose. Therapy was overall well tolerated. Most frequently observed toxicities included anemia (in 43.75% of patients, one Grade 3 event), fatigue (in 43.75% of patients, one Grade 3 event beyond cycle 1) and neuropathy (in 31.25% of patients, one Grade 3 event after cycle 1). Of 15 evaluable patients, one NSCLC patient with paclitaxel exposure at the adjuvant setting had a PR and five patients had SD; median disease stabilization was 143.5 days; three NSCLC patients had SD lasting 165 days or longer. Thus, rationally designed weekly treatment with paclitaxel and bortezomib in solid tumors with MAPK pathway activation, including previously taxane-treated malignancies, is a tolerable regimen with preliminary signals of antitumor activity worthy of further investigation.
MAPK; paclitaxel; bortezomib; BIM; apoptosis
mTOR inhibitors are used clinically to treat renal cancer but are not curative. Here we show that autophagy is a resistance mechanism of human renal cell carcinoma (RCC) cell lines to mTOR inhibitors. RCC cell lines have high basal autophagy that is required for survival to mTOR inhibition. In RCC4 cells, inhibition of mTOR with CCI-779 stimulates autophagy and eliminates RIP kinases (RIPKs) and this is blocked by autophagy inhibition, which induces RIPK- and ROS-dependent necroptosis in vitro and suppresses xenograft growth. Autophagy of mitochondria is required for cell survival since mTOR inhibition turns off Nrf2 antioxidant defense. Thus, coordinate mTOR and autophagy inhibition leads to an imbalance between ROS production and defense, causing necroptosis that may enhance cancer treatment efficacy.
The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP.
In part 1, patients with advanced solid tumors received MK-0731 intravenously over 24 h every 21 days starting at 6 mg/m2, escalating until MTD was reached. In part 2, patients with taxane-resistant tumors received the MTD. Plasma samples were collected to analyze the pharmacokinetics of MK-0731. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0.
In part 1, 21 patients (median age 63 years) were treated with MK-0731 at doses ranging from 6 to 48 mg/m2/24 h for median four cycles. The dose-limiting toxicity was neutropenia and the MTD was 17 mg/m2/24 h. At the MTD, AUC (±SD) was 10.5 (±7.3) μM × hour, clearance (±SD) was 153 mL/min (±84), and t1/2 was 5.9 h. In part 2, 22 patients received the MTD and there were no DLTs. Although there were no objective tumor responses, four patients (with cervical, non-small cell lung, and ovarian cancers) had prolonged stable disease.
MK-0731 at the MTD of 17 mg/m2/day every 21 days in patients with solid tumors had few grade 3 and 4 toxicities with the major DLTs at higher doses being myelosuppression. Anti-tumor efficacy was suggested by the length of stable disease in selected patients with taxane-resistant tumors.
Kinesin spindle protein; Oncology; Neutropenia
Given prior studies demonstrating the marked clinical activity of oral estrogens in prostate cancer, more recent data demonstrating the safety of transdermal estradiol, and the renewed interest in targeting testosterone metabolism and androgen receptor pathways, we report the results of a trial of transdermal estradiol in advanced heavily pre-treated castrate and chemotherapy refractory patients.
Patients with prostate cancer progressing after androgen ablation therapy and chemotherapy were treated with transdermal estradiol patches (0.4 mg per 24 hours total) applied weekly and assessed for tolerability and biochemical activity.
Twenty-two patients were treated on study with all patients evaluable for safety and 20 patients evaluable for response. All patients had aggressive and resistant disease, as demonstrated by a median PSA of 170 ng/mL (range 14 to 5030 ng/mL), with more than 60% having been treated with two or more prior chemotherapy regimens, and 20% with visceral disease. Nine patients had a decrease in PSA, of which two patients had a PSA response defined as a decline in PSA by 50%. Therapy was well tolerated and no thrombotic events were observed.
In heavily pre-treated patients with advanced castrate and chemotherapy refractory metastatic prostate cancer, transdermal estradiol was safe and had biochemical activity. These data support further studies to understand if transdermal estradiol can be useful following multiple standard therapies.
estradiol; abiraterone; testosterone; prostate cancer
An investigational 10% liquid intravenous immunoglobulin (IVIG) was studied in 63 patients with primary immunodeficiency (PID) at 15 study sites.
Patients were treated every 3 or 4 weeks with 254–1029 mg/kg/infusion of IVIG.
Overall, Biotest-IVIG infusions were well tolerated. The proportion of infusions that were associated with adverse events during infusion, and up to 72 h after infusion, including those unrelated to study product, was 27.7% with an upper 95% confidence limit ≤30.6%. Two serious bacterial infections (SBIs) were observed resulting in a serious bacterial infection rate of 0.035 per person per year and an upper one-sided 99% confidence limit of ≤0.136 SBI/patient/year. The number of days of work or school missed due to infection were relatively low at 2.28 days/patient/year. Two patients were hospitalized for infection producing a rate of 0.21 hospitalization days/patient/year. The IgG half-life was approximately 30 days with variation among individuals.
Pharmacokinetic parameters of specific antibody activities were essentially the same as those of total IgG. Biotest-IVIG is safe and effective in the treatment of PID.
Intravenous immunoglobulin (IVIG); primary immunodeficiency (PID); clinical trial; safety; efficacy; pharmacokinetics
Night-to-night variability in sleep of children with attention deficit hyperactivity disorder (ADHD) may be a mediator of behavioral phenotype. We examined the potential association between alertness, sleep, and eating behaviors in children with ADHD and comorbid problems.
Sleep was monitored by actigraphy for 7 days. Questionnaires were used to assess sleep complaints, habits and food patterns by parental report, and sleep complaints and sleepiness by child report.
The group comprised 18 children, including 15 boys, aged 9.4 ± 1.7 years, 88.9% Caucasian, who took one or multiple medications. Children slept on average for 6 hours and 58 minutes with a variability of 1 hour 3 minutes relative to the mean, and their sleepiness scores were highly variable from day to day. Most children had a normal body mass index (BMI). Sleepiness and BMI were associated with sleep schedules and food patterns, such that they accounted for 76% of variance, predominantly by the association of BMI with mean wake after sleep onset and by bedtime sleepiness, with wake after sleep onset variability. Similarly, 97% of variance was shared with eating behaviors, such as desserts and snacks, and fast food meals were associated with morning sleepiness.
Disrupted sleep and sleepiness appears to favor unhealthy food patterns and may place children with ADHD at increased risk for obesity.
sleep; child; attention deficit hyperactivity disorder; actigraphy
Polymorphism of the dopamine transporter genotype (DAT1) confers a small but significant susceptibility to Attention Deficit Hyperactivity Disorder (ADHD). We examined whether the volume of the head of caudate, a striatal structure with high DAT expression that is important for inhibitory function, differs by DAT1 in a children diagnosed with the disorder relative to age and IQ matched controls.
Volume of the head of caudate was delineated in the right and left hemisphere and compared between 7–13 year old children with and without ADHD (Combined type) who were carriers of two (10/10) or one (9/10) copy of the 10-repeat DAT1 allele.
Caudate volumes were overall smaller 10/10 than 9/10 children, particularly in the left than right hemisphere. While DAT1 effects did not vary by ADHD diagnosis, overall caudate volumes were smaller in ADHD relative to control children.
Altered caudate development associated with 10-repeat homozygosity of DAT1 may contribute susceptibility to ADHD.
Brain; structure; VNTR; polymorphism; striatal
Inheriting two (10/10) relative to one (9/10) copy of the 10-repeat allele of the dopamine transporter genotype (DAT1) is associated with Attention Deficit Hyperactivity Disorder, a childhood disorder marked by poor executive function. We examined whether functional anatomy underlying working memory, a component process of executive function, differed by DAT1 in 7-12 year-old typically developing children. 10/10 and 9/10 carriers performed a verbal n-back task in two functional magnetic resonance imaging (fMRI) runs varying in working memory load, high (2-back vs. 1-back) and low (1-back vs. 0-back). Performance accuracy was superior in 9/10 than 10/10 carriers in the high but not low load runs. Examination of each run separately revealed that frontal-striatal-parietal regions were more activated in 9/10 than 10/10 carriers in the high load run; the groups did not differ in the low load run. Examination of load effects revealed a DAT1 X Load interaction in the right hemisphere in the caudate, our a priori region of interest. Exploratory analysis at a more liberal threshold revealed this interaction in other basal ganglia regions (putamen, and substantial nigra/subthalamic nuclei – SN/STN) and in medial parietal cortex (left precuneus). The striatal and parietal regions were more activated in 9/10 carriers under high than low load, and DAT1 differences (9/10 > 10/10) were evident only under high load. In contrast, SN/STN tended to be more activated in 10/10 carriers under low than high load and DAT1 differences (10/10 > 9/10) were evident only under low load. Thus, 10-repeat homozygosity of DAT1 was associated with reduced performance and a lack of increased basal ganglia involvement under higher working memory demands.
caudate; fMRI; N-back; functional polymorphism; DAT1; executive function
Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin.
Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m2) and cisplatin (75 mg/m2) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs).
Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response.
Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases.
One strategy for understanding variability in attention-deficit hyperactivity disorder (ADHD) medication response, and therefore redressing the current trial-and-error approach to ADHD medication management, is to identify genetic moderators of treatment. This article summarizes ADHD pharmacogenetic investigative efforts to date, which have primarily focused on short-term response to methylphenidate and largely been limited by modest sample sizes. The most well studied genes include the dopamine transporter and dopamine D4 receptor, with additional genes that have been significantly associated with stimulant medication response including the adrenergic α2A-receptor, catechol-O-methyltransferase, D5 receptor, noradrenaline (norepinephrine) transporter protein 1 and synaptosomal-associated protein 25 kDa.
Unfortunately, results of current ADHD pharmacogenetic studies have not been entirely consistent, possibly due to differences in study design, medication dosing regimens and outcome measures. Future directions for ADHD pharmacogenetics investigations may include examination of drug-metabolizing enzymes and a wider range of stimulant and non-stimulant medications. In addition, researchers are increasingly interested in going beyond the individual candidate gene approach to investigate gene-gene interactions or pathways, effect modification by additional environmental exposures and whole genome approaches. Advancements in ADHD pharmacogenetics will be facilitated by multi-site collaborations to obtain larger sample sizes using standardized protocols. Although ADHD pharmacogenetic efforts are still in a relatively early stage, their potential clinical applications may include the development of treatment efficacy and adverse effect prediction algorithms that incorporate the interplay of genetic and environmental factors, as well as the development of novel ADHD treatments.
Attention-deficit hyperactivity disorder (ADHD) is a highly heritable disorder of impaired behavioral inhibition, increased motor activity, and inattention. The norepinephrine transporter (NET, SLC6A2) represents an important candidate gene for contribution to ADHD because it regulates catecholamine extracellular and tissue concentrations and contributes to executive functions disrupted in ADHD, and NET is a target for most effective ADHD therapeutics. We identified four NET coding single nucleotide polymorphisms (SNPs) in two ADHD sample sets, two SNPs produce protein variants (T283M, V245I), one of which, T283M, is a novel variant. Examination of the maternal family members through whom the T283M mutation was transmitted, provided no additional ADHD diagnoses. Given the previous identification of a NET mutation that contributes to a familial tachycardia syndrome, we examined autonomic function to reveal in the proband the highest standing-induced increase in heart rate among the ADHD subjects examined. We measured [3H]NE and [3H]dopamine transport for T283M, V245I, and a previously identified NET variant, T283R. T283M and V245I demonstrated decreased substrate transport, as did T283R, suggesting that the T283 residue is sensitive to mutation. Identification of polymorphic sites within NET, specifically those that produce functional consequences, is one critical step in elucidating the genetic variation contributing to the heritable component of diseases such as ADHD.
norepinephrine; transporter; gene; SNP; polymorphism; attention-deficit hyperactivity disorder
National-level data that characterize contemporary prostate cancer patients are limited. We used 2004–2005 data from the Surveillance, Epidemiology, and End Results Program to generate a contemporary profile of prostate cancer patients (N = 82 541) and compared patient characteristics of this 2004–2005 population with those of patients diagnosed in 1998–1989 and 1996–1997. Among newly diagnosed patients in 2004–2005, the majority (94%) had localized (ie, stage T1 or T2) prostate cancer and a median serum prostate-specific antigen (PSA) level of 6.7 ng/mL. Between 1988–1989 and 2004–2005, the average age at prostate cancer diagnosis decreased from 72.2 to 67.2 years, and the incidence rate of T3 or T4 cancer decreased from 52.7 per 100 000 to 7.9 per 100 000 among whites and from 90.9 per 100 000 to 13.3 per 100 000 among blacks. In 2004–2005, compared with whites, blacks were more likely to be diagnosed at a younger age (mean age: 64.7 vs 67.5 years, difference = 2.7 years, 95% confidence interval [CI] = 2.5 to 2.9 years, P < .001) and to have a higher PSA level at diagnosis (median PSA level: 7.4 vs 6.6 ng/mL, difference = 0.8 ng/mL, 95% CI = 0.6 to 1.0 ng/mL, P < .001). In conclusion, more men were diagnosed with prostate cancer at a younger age and earlier stage in 2004–2005 than in earlier years. The racial disparity in cancer stage at diagnosis has decreased statistically significantly over time.
There is no effective second line systemic chemotherapy for patients with disease progression following cisplatin-based chemotherapy. A phase II trial of sorafenib was performed to determine the activity and toxicity of this agent in a multiinstitutional setting in patients previously treated with 1 prior chemotherapy regimen.
27 patients with advanced urothelial carcinoma were treated with sorafenib 400 mg orally twice daily continuously until progression or unacceptable toxicity.
There were no objective responses observed. The 4-month progression free survival (PFS) rate was 9.5% , median overall survival of the group was 6.8 months. There were no therapy related deaths, and common grade 3 toxicities included fatigue and hand-foot syndrome
Although sorafenib as a single agent has minimal activity in patients with advanced urothelial cancer in the second line setting, further investigation of tyrosine kinase inhibitors using different trial designs with PFS endpoints is warranted.
urothelial cancer; sorafenib
The dopamine transporter locus (DAT1) has been studied as a risk factor for attention-deficit/hyperactivity disorder (ADHD) and in pharmacogenetic studies of stimulant response. Several prospective studies have reported an association between the homozygous 9 repeat allele of the DAT1 3′ untranslated region (UTR) variable number tandem repeat (VNTR) (DAT1 3′) and decreased efficacy of methylphenidate (MPH). We hypothesized that children with the 9/9 genotype would display higher rates of specific stimulant side effects. Data on adverse events and DAT1 3′ genotypes were combined from two, double-blind, placebo-controlled, crossover studies of MPH conducted in child psychiatric outpatient clinics in Montreal and Washington, D.C. There were 177 participants, 5–16 years old (mean age = 8.99, standard deviation [SD] = 2), with ADHD. Parents completed the Stimulant Side Effect Scale (SERS) after a week of placebo and a week of MPH treatment. Principal components analysis of the SERS resulted in three factors: Emotionality, Somatic Complaints, and Over-focused. Children with the 9/9 genotype displayed higher scores on the Emotionality factor during placebo than children with the 9/10 and the 10/10 genotype, and their Emotionality scores increased further during MPH treatment (F[2,151] = 3.24, p < 0.05). Children with the 10/10 genotype displayed a significant increase in Somatic Complaint factor scores during MPH treatment relative to the other genotype groups (F[2,150] = 3.4, p < 0.05). These data provide suggestive evidence that DAT1 variants are differentially associated with specific stimulant side effects. Children with the 9/10 genotype displayed less severe stimulant side-effect ratings than either of the homozygous groups, who each displayed increased susceptibility to different types of adverse events. Preliminary evidence suggests that pharmacogenetic analysis using DAT1 variants shows promise for identifying individuals at increased or decreased risk for poor tolerability.
Autophagy is a starvation induced cellular process of self-digestion that allows cells to degrade cytoplasmic contents. The understanding of autophagy, as either a mechanism of resistance to therapies that induce metabolic stress, or as a means to cell death, is rapidly expanding and supportive of a new paradigm of therapeutic starvation.
To determine the effect of therapeutic starvation in prostate cancer, we studied the effect of the prototypical inhibitor of metabolism, 2-deoxy-D-glucose (2DG), in multiple cellular models including a transfected pEGFP-LC3 autophagy reporter construct in PC-3 and LNCaP cells.
We found that 2DG induced cytotoxicity in PC-3 and LNCaP cells in a dose dependent fashion. We also found that 2DG modulated checkpoint proteins cdk4, and cdk6. Using the transfected pEGFP-LC3 autophagy reporter construct, we found that 2DG induced LC3 membrane translocation, characteristic of autophagy. Furthermore, knockdown of beclin1, an essential regulator of autophagy, abrogated 2DG induced autophagy. Using Western analysis for LC3 protein, we also found increased LC3-II expression in 2DG treated cells, again consistent with autophagy. In an effort to develop markers that may be predictive of autophagy, for assessment in clinical trials, we stained human prostate tumors for Beclin1 by immunohistochemistry (IHC). Additionally, we used a digitized imaging algorithm to quantify Beclin1 staining assessment.
These data demonstrate the induction of autophagy in prostate cancer by therapeutic starvation with 2DG, and support the feasibility of assessment of markers predictive of autophagy such as Beclin1 that can be utilized in clinical trials.
prostate cancer; deoxyglucose; beclin1; autophagy; glycolysis; metabolism