Work in progress: radioprotection of human breast cancer cells by elevation of intracellular cyclic AMP

MCF-7 human breast cancer cells that were treated for one hour prior to X irradiation with the cyclic AMP-inducing agent 1-methyl-3-isobutylxanthine displayed a slight but significant increase in surviving fraction over untreated controls at each radiation dose level. This was accompanied by a two-fold increase in the level of intracellular cyclic AMP.     

High prevalence of SV40 infection in patients with nodal non-Hodgkin's lymphoma but not acute leukemia independent of contaminated polio vaccines in Taiwan

Recent studies have linked simian virus 40 (SV40) to non-Hodgkin's lymphoma (NHL), especially in countries in which people were exposed to contaminated polio vaccines prior to 1963. In Taiwan, nearly all children were not exposed to contaminated polio vaccine during this period; the relationship between SV40 infection and hematological malignancies is unclear and deserves to be studied. Using PCR amplification of SV40 large T antigen DNA, confirmed by Southern blot hybridization and sequence analysis, 91 frozen lymph nodes from NHL patients were examined. Thirteen (14.3 percent) showed positive for SV40. All other test samples, including diagnostic bone marrow from patients with acute leukemia, peripheral blood from 10 relatives of SV40 positive-patients and 91 age-matched normal volunteers, and 5 reactive hyperplastic lymphoid tissues, showed negative. These results may reflect that human-to-human transmission of SV40 is independent of contaminated polio vaccines; and SV40 is possibly associated with the development of NHL in Taiwan (p = 0.0001). Prospective studies are needed to determine the prevalence of SV40 infections in our and other human populations and to explore the means of transmission of the virus.     

Plasminogen activator inhibitor-1 promoter polymorphism is not associated with the aggressiveness of disease in prostate cancer

AimsPAI-1 (plasminogen activator inhibitors-1) regulates plasminogen activation, and is related to tumour development. This study aims to test whether the promoter polymorphism in the PAI-1 gene is related to the aggressiveness of disease in prostate cancer.Materials and methodsIn the present study, Taqman SNP genotyping assay was used to detect PAI-1 4G/5G polymorphism in DNA from paraffin-embedded tissues of 98 Caucasian patients with prostate cancer.ResultsThe distribution of the genotypes is in Hardy–Weinberg equilibrium. The genotype had no statistically significant relationship with other prognostic factors. Similar risks for recurrence were seen in individuals with the 4G/4G and 4G/5G genotypes compared to those with 5G/5G genotype (odds ratio [OR] 2.65, 95% CI: 0.41–16.94, P = 0.30; OR = 2.19, 95% CI: 0.38–12.49, P = 0.38).ConclusionWe concluded that PAI-1 promoter polymorphism is not associated with the aggressiveness of disease in prostate cancer.     

Comparison of the effects of PAR1 antagonists, PAR4 antagonists, and their combinations on thrombin-induced human platelet activation

Thrombin activates human platelets through proteolytic activation of two protease-activated receptors (PARs), PAR1 and PAR4. In the present study, we show that, RWJ-56110, a potent synthetic PAR1 antagonist, inhibited platelet aggregation caused by a low concentration (0.05 U/ml) of thrombin, but lost its effectiveness when higher concentrations of thrombin were used as stimulators. YD-3, a non-peptide PAR4 antagonist, alone had little or no effect on thrombin-induced platelet aggregation, significantly enhanced the anti-aggregatory activity of PAR1 antagonist. In addition, we demonstrate for the first time that P-selectin expression in thrombin-stimulated platelets can be synergistically prevented by combined treatment of PAR1 antagonist and PAR4 antagonist. These results indicate that thrombin-induced platelet activation cannot be effectively inhibited by just blocking either single thrombin receptor pathway, and suggest a rationale for potential combination therapy in arterial thrombosis.     

Pathophysiology, clinical presentation and treatment of gout

Gout is a common form of inflammatory arthritis that has been managed primarily in general medical practices for centuries. It appears that there has been an increasing prevalence of gout over the past decades, implying a growing public health burden. Accurate diagnosis and recognition of the various stages and manifestations of gout enable realistic goal setting for management. Recent evidence suggests new risk factors and potentially refutes others. Management of gout requires characterising and modifying risk factors and associated disorders, and commonly initiating drug therapy. Pharmacotherapy of gout includes the management of acute flares with anti-inflammatory agents such as NSAIDs and glucocorticoids and long-term treatment with urate-lowering drugs. Although pharmacotherapy is generally safe and effective, there are caveats and limitations to all gout therapies. Patient non-adherence and errors with the use of drugs for gout treatment are important factors leading to medical failures. With early intervention, careful monitoring and patient education, gout is a condition that can be managed very effectively. The advent of new drugs (such as febuxostat and urate oxidase [uricase]) and enhanced understanding of the pathogenesis of gout continue to improve our therapeutic options, particularly in a subset of patients with refractory disease and those who are intolerant to currently available medications.     

Pharmacokinetics of selected stilbenes: rhapontigenin, piceatannol and pinosylvin in rats

The pharmacokinetics of piceatannol, pinosylvin and rhapontigenin were characterized in male Sprague-Dawley rats after single intravenous doses of 10 mg kg(-1) of each stilbene. Serial blood samples were collected via a catheter inserted into the right jugular vein and plasma samples were analysed for the selected stilbenes concentrations using reverse phase HPLC methods. After an acute intravenous dose of piceatannol, plasma AUC, urine t(1/2), CL and V(d) were 8.48+/-2.48 micro g h mL(-1), 19.88+/-5.66 h, 2.13+/-0.92 Lh(-1) kg(-1) and 10.76+/-2.88 L kg(-1)(mean+/-s.e.m.), respectively. The acute intravenous dose of pinosylvin yielded the plasma AUC, urine t(1/2), CL and V(d) values of 5.23+/-1.20 micro g h mL(-1), 13.13+/-2.05 h, 1.84+/-0.44 Lh(-1) kg(-1) and 2.29+/-0.56 L kg(-1)(mean+/-s.e.m.), respectively. Rhapontigenin intravenous dosing yielded the plasma AUC, urine t(1/2), CL and V(d) values of 8.39+/-0.10 micro g h mL(-1), 25.31+/-1.46 h, 1.18+/-0.035 Lh(-1) kg(-1) and 11.05+/-0.17 L kg(-1)(mean+/-s.e.m.), respectively. Each stilbene was extensively glucuronidated. These stilbenes were predominantly eliminated via non-urinary routes. All three stilbenes were highly distributed into tissues and were highly extracted by the liver. The detectable plasma half-lives of these xenobiotics appear to be relatively short. However, utilizing urinary concentration-time data, much longer elimination half-lives were evident. The estimates of oral bioavailability characterize these stilbenes as poorly bioavailable compounds.     

Nontoxic Suramin as a Chemosensitizer in Patients: Dosing Nomogram Development

Purpose We reported that suramin produced chemosensitization at nontoxic doses. This benefit was lost at the ∼10-fold higher, maximally tolerated doses (MTD). The aim of the current study was to identify in patients the chemosensitizing suramin dose that delivers 10–50 μM plasma concentrations over 48 h. Methods Nonsmall cell lung cancer patients were given suramin, paclitaxel, and carboplatin, every 3 weeks. The starting chemosensitizing suramin dose was estimated based on previous results on MTD suramin in patients, and adjusted by using real-time pharmacokinetic monitoring. A dosing nomogram was developed by using population-based pharmacokinetic analysis of phase I results (15 patients, 85 treatment cycles), and evaluated in phase II patients (19 females, 28 males, 196 treatment cycles). Results The chemosensitizing suramin dose showed a terminal half-life of 202 h and a total body clearance of 0.029 L h⁻¹ m⁻² (higher than the 0.013 L h⁻¹ m⁻² value for MTD of suramin). The dosing nomogram, incorporating body surface area as the major covariate of intersubject variability and the time elapsed since the previous dose (to account for the residual concentrations due to the slow elimination), delivered the target concentrations in >95% of treatments. Conclusions The present study identified and validated a dosing nomogram and schedule to deliver low and nontoxic suramin concentrations that produce chemosensitization in preclinical models.