Intracellular protein binding patterns of the anticancer ruthenium drugs KP1019 and KP1339.

The ruthenium compound KP1019 has demonstrated promising anticancer activity in a pilot clinical trial. This study aims to evaluate the intracellular uptake/binding patterns of KP1019 and its sodium salt KP1339, which is currently in a phase I-IIa study. Although KP1339 tended to be moderately less cytotoxic than KP1019, IC(50) values in several cancer cell models revealed significant correlation of the cytotoxicity profiles, suggesting similar targets for the two drugs. Accordingly, both drugs activated apoptosis, indicated by caspase activation via comparable pathways. Drug uptake determined by inductively coupled plasma mass spectrometry (ICP-MS) was completed after 1 h, corresponding to full cytotoxicity as early as after 3 h of drug exposure. Surprisingly, the total cellular drug uptake did not correlate with cytotoxicity. However, distinct differences in intracellular distribution patterns suggested that the major targets for the two ruthenium drugs are cytosolic rather than nuclear. Consequently, drug-protein binding in cytosolic fractions of drug-treated cells was analyzed by native size-exclusion chromatography (SEC) coupled online with ICP-MS. Ruthenium-protein binding of KP1019- and KP1339-treated cells distinctly differed from the platinum binding pattern observed after cisplatin treatment. An adapted SEC-SEC-ICP-MS system identified large protein complexes/aggregates above 700 kDa as initial major binding partners in the cytosol, followed by ruthenium redistribution to the soluble protein weight fraction below 40 kDa. Taken together, our data indicate that KP1019 and KP1339 rapidly enter tumor cells, followed by binding to larger protein complexes/organelles. The different protein binding patterns as compared with those for cisplatin suggest specific protein targets and consequently a unique mode of action for the ruthenium drugs investigated.

Antivascular agents for non-small-cell lung cancer: current status and future directions.

BACKGROUND: Despite improvements in surgery and chemo(radio)therapy which have allowed for modest advances in the treatment of patients with non-small-cell lung cancer (NSCLC), survival remains poor and further improvements are needed. Attention over recent years has focused, therefore, on targeted therapies, with notable success in the development of antivascular drugs. OBJECTIVE: To summarize the current knowledge on antivascular therapy in patients with NSCLC. METHOD: Review of randomized controlled trials exploring treatment of NSCLC patients with antivascular drugs. RESULTS/CONCLUSION: Bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), when added to cytotoxic chemotherapy, was the first treatment to prolong the overall survival of patients with advanced NSCLC beyond 12 months, a significant breakthrough in the management of advanced NSCLC. Small-molecule tyrosine kinase inhibitors and alternative antivascular strategies such as VEGF-trap and vascular disrupting agents are also being investigated and have shown promise in clinical trials. This review summarizes the most recent and important findings in antivascular agents in NSCLC.

Pulmonary retransplantation: is it worth the effort? A long-term analysis of 46 cases.

BACKGROUND: Pulmonary retransplantation remains the only therapeutic option in some cases of severe primary graft dysfunction (PGD), advanced bronchiolitis obliterans syndrome (BOS), and in some cases of severe airway problems (AWP), mainly cicatriceal stenosis. However, its value has been questioned due to the overall scarcity of donor organs and reports indicating unsatisfactory outcome. We analyzed our institutional experience with pulmonary retransplantation to evaluate its value for different indications. METHODS: We retrospectively analyzed all 46 patients undergoing pulmonary retransplantation from the 567 consecutive primary lung or heart-lung transplantations performed in our department from August 1995 to August 2006. We stratified patients according to indication for retransplantation and analyzed the outcome. RESULTS: Forty-six patients (mean age 41 +/- 16 years, 18 men and 28 women) underwent pulmonary retransplantation (14 bilateral lung transplantations, 32 single-lung transplantations) for primary graft dysfunction (n = 23), bronchiolitis obliterans syndrome (n = 19) and airway problems (n = 4). Mean time to retransplantation was 26 +/- 27 days in the PGD group, 1,069 +/- 757 days in the BOS group and 220 +/- 321 days in the AWP group. Thirty-day, 1-year and 5-year survival rates after retransplantation were 52.2%, 34.8% and 29.0% in the PGD group and 89.2%, 72.5% and 61.3% in the BOS group, respectively. All 4 patients in the AWP group are presently alive (BOS vs PGD: p = 0.02; BOS vs AWP: p = 0.27; PGD vs AWP: p = 0.06). CONCLUSIONS: Pulmonary retransplantation for bronchiolitis obliterans offers long-term survival rates in the range of primary lung transplantation for selected patients. Long-term survival rates for retransplantation due to PGD are significantly lower, warranting restrictive use in this setting. In our experience with a limited number of patients, retransplantation for airway problems has shown excellent results. Pulmonary retransplantation for chronic problems is a plausible approach, provided that patients are carefully selected. Retransplantation for PGD should be avoided.

Haemodynamic complications after pneumonectomy: atrial inflow obstruction and reopening of the foramen ovale.

BACKGROUND: Haemodynamic impairments after pneumonectomy are rare complications and present in different forms. Due to a low awareness of these potential complications their diagnosis is difficult and often established late. The most important forms are: firstly reopening of a previously closed foramen ovale (PFO) caused by a combination of changed anatomic position of the left atrium and elevated pulmonary artery pressure leading to a significant right-left shunt; secondly diaphragmatic relaxation can lead to a dislocation of the liver into the right hemithorax, compressing the right atrium with subsequent inflow obstruction. METHODS: We retrospectively analysed our patient cohort from 1997 to 2006 for occurrence of haemodynamic complications requiring surgical intervention after pneumonectomy. RESULTS: Five hundred and forty-six pneumonectomies were performed in our centre during the observation period. Five patients (1 female, 4 male, age 59+/-9 years) with haemodynamic complications were identified. Two of those patients were referred with haemodynamic complications after pneumonectomy was performed in a peripheral centre. All patients had undergone right pneumonectomy for NSCLC (n=4) or atypical carcinoid (n=1). Two patients were readmitted 3 months and 2 years postoperatively due to increasing platypnoea and orthodeoxia. After closure of the reopened foramen ovale, which was found as the underlying pathological mechanism, respiratory symptoms were resolved. One patient required reintubation 2h postoperatively; after surgical closure of a PFO the respiratory situation significantly improved. One patient was readmitted due to right atrial inflow obstruction 17 months after right pneumonectomy. Underlying cause was a severe diaphragmatic relaxation with compression of the atrium by the liver. After diaphragmatic plication all symptoms resolved. However 1 year thereafter reoperation for recurrence of diaphragmatic elevation was required. One patient was readmitted 3 months after pneumonectomy and partial atrial resection for cyanosis and dyspnoea. Diagnostics revealed a PFO and a massive raise of the right diaphragm with compression of the right atrium. After surgical correction of the contorted foramen ovale and diaphragmatic plication, symptoms vanished. CONCLUSION: Haemodynamic alterations due to a reopened foramen ovale or right atrial inflow obstruction are rare, however they are severe complications after pneumonectomy. They occur at variable points in time after pneumonectomy. Diagnostic efforts are often made at a late stage due to a low awareness of the problem. Closure of the PFO either surgical or interventional and/or plication of the elevated diaphragm are mandatory. In our experience these complications occur only after right pneumonectomy.

[Surgical treatment of obesity]. / Chirurgische Therapie der Adipositas.

At the beginning of the 21st century, obesity has become an epidemic with the greatest prevalence in the western world. For morbidly obese patients, conservative treatment has yielded disappointing results: On the other hand, bariatric surgery offers a sustained substantial weight loss for these patients. Common bariatric procedures including results and complications are described. Different Bariatric procedures including Gastric Banding, Vertical Banded Gastroplasty, Gastric Bypass, Duodenal Switch and Gastric Pacing are introduced. Bariatric procedures can result in permanent excessive weight loss ranging from 25 to 78% and thus are an effective treatment for morbidly obese patients. Efficacy, morbidity and late term complications, however, should be considered in choosing the most effective bariatric approach.