Drug and Alcohol Rehabilitation: In Vivo Targeting of ADAM9 Gene Expression Using Lentivirus-Delivered shRNA Suppresses Prostate Cancer Growth by Regulating REG4 Dependent Cell Cycle Progression.

In Vivo Targeting of ADAM9 Gene Expression Using Lentivirus-Delivered shRNA Suppresses Prostate Cancer Growth by Regulating REG4 Dependent Cell Cycle Progression.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(1): e53795
Liu CM, Hsieh CL, He YC, Lo SJ, Liang JA, Hsieh TF, Josson S, Chung LW, Hung MC, Sung SY

Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM) 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA) significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4) expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1), which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.
HubMed – drug

The Price of Tumor Control: An Analysis of Rare Side Effects of Anti-CTLA-4 Therapy in Metastatic Melanoma from the Ipilimumab Network.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(1): e53745
Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, Bergmann T, Bockmeyer CL, Eigentler T, Fluck M, Garbe C, Gutzmer R, Grabbe S, Hauschild A, Hein R, Hundorfean G, Justich A, Keller U, Klein C, Mateus C, Mohr P, Paetzold S, Satzger I, Schadendorf D, Schlaeppi M, Schuler G, Schuler-Thurner B, Trefzer U, Ulrich J, Vaubel J, von Moos R, Weder P, Wilhelm T, Göppner D, Dummer R, Heinzerling LM

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.Patient files (n?=?752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patient? delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
HubMed – drug

Initial antihypertensive prescription and switching: a 5 year cohort study from 250,851 patients.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(1): e53625
Wong MC, Tam WW, Cheung CS, Tong EL, Sek AC, John G, Cheung NT, Yan BP, Yu CM, Leeder S, Griffiths S

Adverse effects of antihypertensive therapy incur substantial cost. We evaluated whether any major classes of antihypertensive drugs were significantly associated with switching as a proxy measure of medication side effects in a large Chinese population in Hong Kong.From a clinical database, all adult patients newly prescribed an antihypertensive mono-therapy in Hong Kong between the years 2001-2003 and 2005 were included. Those who paid only one visit, died or stayed in the cohort for <180 days after the prescription, or prescribed more than one antihypertensive agent were excluded. The factors associated with switching at 180 days were evaluated by multivariate regression analyses. Age, gender, payment status, service type, district of residence, drug class, systolic and diastolic blood pressure levels were predictor variables.From 250,851 subjects, 159,813 patients were eligible. A total of 6,163 (3.9%) switched their medications within 180 days. Patients prescribed thiazide diuretics had the highest switching rate (5.6%), followed by ACEIs (4.5%), CCBs (4.4%) and beta-blockers (3.2%). When compared with ACEIs, patients on thiazide diuretics were significantly more likely to be switchers (adjusted odds ratio [AOR] 1.49, 95% C.I. 1.31-1.69, p<0.001), whilst patients prescribed CCBs and beta-blockers were similarly likely to have switching. Following these patients up for 5 years showed that thiazide had the most marked increase in switching rate.The higher rates of switching among thiazide diuretics in this study might raise a probably greater incidence of their adverse effects in this Chinese population, yet other factors might also influence switching rates. Patients prescribed thiazide diuretics for longer term should be observed for their intolerability. HubMed – drug

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