Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.

Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674.

Targeted therapies in the treatment of advanced/metastatic NSCLC.

The treatment of advanced non-small cell lung cancer (NSCLC) has evolved substantially during the last years. Chemotherapy remains the cornerstone of treatment and prolongs survival with a positive impact on quality of life. However, we seem to have reached a plateau of activity in the treatment of NSCLC. Recently, the addition of bevacizumab or cetuximab to chemotherapy doublets has improved the outcome in selected patients with advanced NSCLC. Furthermore, the use of erlotinib and gefitinib is an alternative for second line treatment. Advances in our understanding of molecular biology of cancer and mechanisms of tumourigenesis have further enabled the discovery of several potential molecular targets and development of novel 'targeted therapies'. The purpose of this study is to review current data on the role of targeted therapies in the treatment of advanced NSCLC.

Calcium ion downregulates soluble guanylyl cyclase activity: evidence for a two-metal ion catalytic mechanism.

The inhibition of soluble guanylyl cyclase by Ca2+ has been kinetically characterized and the results support a two-metal-ion catalytic mechanism for formation of cGMP. Ca2+ reversibly inhibits both the basal and NO-stimulated forms of bovine lung soluble guanylyl cyclase. Inhibition is independent of the activator identity and concentration, revealing that Ca2+ interacts with a site independent of the heme regulatory site. Inhibition by Ca2+ is competitive with respect to Mg2+ in excess of substrate, with Kis values of 29 +/- 4 and 6.6 +/- 0.6 microM for the basal and activated states, respectively. Ca2+ inhibits noncompetitively with respect to the substrate MgGTP in both activity states. The qualitatively similar inhibition pattern and quantitatively different Ki values between the basal and NO-stimulated states suggest that the Ca2+ binding site undergoes some structural modification upon activation of the enzyme. The competitive nature of Ca2+ inhibition with respect to excess Mg2+ is consistent with a two-metal-ion mechanism for cyclization.

Effect of heme oxygenase inhibitors on soluble guanylyl cyclase activity.

NO is the physiological activator of soluble guanylyl cyclase (sGC) thereby acting as a signaling molecule in the nervous and cardiovascular systems. Despite its poor sGC-activating ability, CO, produced by the enzyme heme oxygenase (HO), has also been implicated as a physiological stimulator of sGC in neurotransmission and vasorelaxation. Zinc protoporphyrin IX (ZnPPIX) and tin protoporphyrin IX (SnPPIX) are competitive HO inhibitors and have been used in studies implicating a messenger role for CO in the brain and periphery; however, little is known about the specificity of these metalloporphyrins. In the present study, the effects of ZnPPIX and SnPPIX on sGC activity have been investigated in vitro. Interestingly, purified sGC is markedly activated by SnPPIX (20- to 30-fold) but has a very low affinity for this metalloporphyrin (Ka = 4.9 microM); high concentrations of SnPPIX (25 microM) still activated the enzyme. On the other hand, sGC has a high affinity for ZnPPIX (Ka = 16.1 nM). ZnPPIX activates heme-containing sGC weakly at low (nM) concentrations (3- to 4-fold) but at higher concentrations, ZnPPIX is a potent inhibitor; at 2.5 microM, it inhibits the basal activity of sGC by about 80%. These results imply that HO inhibitors may affect cGMP levels independently of HO activity.

General synthesis of 3-substituted alkenyl GABA as potential anticonvulsants.

Stereospecific synthesis of cis and trans 3-substituted vinyl-gamma-aminobutyric acid analogs were obtained by either a Claisen rearrangement or a Wittig reaction from common diene precursors.