Multicenter Phase II Clinical Trial of Isolated Lung Perfusion in Patients With Lung Metastases.

Background: Up to 66% of patients show local pulmonary disease progression after pulmonary metastasectomy. Regional treatment with isolated lung perfusion (ILuP) may improve local control with minimal systemic adverse effects. The aims of this study were to evaluate local and distant control after ILuP, determine the effect on overall survival compared with historical controls, and confirm the safety and feasibility of ILuP.

Selective pulmonary artery perfusion with melphalan is equal to isolated lung perfusion but superior to intravenous melphalan for the treatment of sarcoma lung metastases in a rodent model.

Objectives: Isolated lung perfusion (ILuP) and selective pulmonary artery perfusion (SPAP) are experimental surgical techniques to deliver high-dose chemotherapy selectively to the lung for the treatment of lung metastases. ILuP with melphalan (MN) has shown to be feasible in clinical studies but can only be used once because it is invasive. SPAP as an endovascular technique can be repeated several times, but no results have been reported so far.

Isolated hypoxic hepatic perfusion with retrograde outflow in patients with irresectable liver metastases; a new simplified technique in isolated hepatic perfusion.

Background: Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure.

Pharmacokinetics of gemcitabine when delivered by selective pulmonary artery perfusion for the treatment of lung cancer.

Lung cancer represents a major health problem. Cytostatic and radiotherapeutic treatment is limited because of dose-limiting systemic toxicity and surgery as a result of its invasive nature. Therefore, we developed a catheterization model of selective pulmonary artery perfusion (SPAP) combining the properties of isolated lung perfusion and i.

Proteomics in cancer research: methods and application of array-based protein profiling technologies.

With the human genome sequence now determined, the field of molecular medicine is moving beyond genomics to proteomics, the large-scale analysis of proteins. It is now possible to examine the expression of more than 1000 proteins using mass spectrometry technology coupled with various separation methods. Microarray technology is a new and efficient approach, for extracting relevant biomedical data and has a wide range of applications.

Simultaneous determination of AMN107 and Imatinib (Gleevec, Glivec, STI571) in cultured tumour cells using an isocratic high-performance liquid chromatography procedure with UV detection.

A reversed phase high-performance liquid chromatographic (HPLC) method with UV detection was developed for the simultaneous determination of imatinib (Gleevec, Glivec, STI571) and AMN107 in cultured tumour cells, using clozapine as an internal standard. The compounds of interest were extracted by liquid-liquid extraction using TOXI-TUBES((R)) A extraction tubes. Chromatographic separation was performed on a Phenomenex Gemini C18 reversed phase column (150 mm x 2.

Modified approach of administering cytostatics to the lung: more efficient isolated lung perfusion.

Background: Isolated lung perfusion (ILuP) is an experimental technique for the treatment of pulmonary metastases. We hypothesized that part of the drug taken up by the lung during ILuP is washed out during the flush procedure. Therefore, we investigated gemcitabine uptake at different inflow concentrations, and the effect of delayed clamp release after ILuP on lung levels was studied.

Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion.

Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects.

Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib.

Objective: Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate-binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib.

Methods: Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Steady-state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d.

Everolimus alters imatinib blood partition in favour of the erythrocyte.

The signal transduction inhibitor imatinib is one of the latest breakthroughs in cancer pharmacotherapy. It is administered orally over prolonged periods of time for the treatment of gastro-intestinal stromal tumours. Routine therapeutic drug monitoring of blood plasma versus red blood cells over several years by liquid chromatography coupled tandem mass spectrometry has high-lighted a very intriguing phenomenon.

Imatinib (Gleevec, Glivec) tumour tissue analysis by measurement of sediment and by liquid chromatography tandem mass spectrometry.

The analysis of the signal transduction inhibitor imatinib in patient tumour tissue using LC and MS/MS is described. The anticancer agent is eluted over RP-C18 within 2 mm together with its internal standard STI571-d8. Calibration curves were prepared in red blood cells (RBC).

Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines.

Imatinib and AMN107 are protein tyrosine kinase inhibitors which reduce KIT autophosphorylation with similar potency. This report describes the cellular uptake of these compounds in two human gastrointestinal stromal tumor (GIST)-derived cell lines (GIST882 and GIST GDG1), which both express constitutively activated KIT. In GIST882 and GIST GDG1 cell lines, HPLC analysis revealed AMN107 intracellular concentrations to be 7- and 10-fold greater than those of imatinib.

In vitro partition of irinotecan (CPT-11) in human volunteer blood: the influence of concentration, gender and smoking.

We have performed in vitro incubations of blood from male and female volunteers, smokers and non-smokers, with irinotecan at a gradient of different concentrations in order to investigate changes of partition between red blood cells (RBCs), total plasma and the free fraction. Since irinotecan (CPT-11) is not metabolized in vitro, there is no data available on its active metabolite SN-38. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by fluorescence detection was used to determine the concentration of the drug in the different blood constituents.

In vitro partition of docetaxel and gemcitabine in human volunteer blood: the influence of concentration and gender.

We have performed in vitro incubations of blood from male and female volunteers with gemcitabine and docetaxel alone, and in combination, at different concentration gradients in order to investigate changes in partition between red blood cells (RBCs), total plasma and the free fraction. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by UV detection was used to determine the concentrations of both drugs in the different blood constituents. The partition ratio [the concentration in the erythrocytes divided by the concentration in plasma (E/P)] was calculated.

Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps.

Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold).

Anterograde versus retrograde isolated lung perfusion with melphalan in the WAG-Rij rat.

Objective: Isolated lung perfusion (ILuP) is an experimental technique currently tested to increase the 5-year survival of 40% after surgical resection of pulmonary metastases from certain solid tumors. The standard technique of anterograde perfusion was compared with retrograde isolated lung perfusion in which the drug is introduced through the pulmonary veins while the effluent is collected from the pulmonary artery. Since the lung has a dual arterial circulation through the pulmonary artery and bronchial circulation, perfusion through the pulmonary veins can result in a more homogeneous distribution throughout the lung with subsequent higher melphalan concentration.

Regional differences of melphalan lung levels after isolated lung perfusion in the rat.

Background: Efficacy studies of isolated lung perfusion (ILuP) with melphalan showed superior results compared to intravenous therapy. However, the influence of pharmacokinetic parameters on the final melphalan lung concentration (FMLC) is unknown. In this study, we studied the impact of three different perfusion parameters on the FMLC in different areas of the lung.

The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment.

Therapeutic drug monitoring generally focuses on the plasma compartment only. Differentiation between the total plasma concentration and the free fraction (plasma water) has been described for a number of limited drugs. Besides the plasma compartment, blood has also a cellular fraction which has by far the largest theoretical surface and volume for drug transport.

Synergistic antitumor activity of histamine plus melphalan in isolated limb perfusion: preclinical studies.

Background: We have previously shown how tumor response of isolated limb perfusion (ILP) with melphalan was improved when tumor necrosis factor alpha (TNF-alpha) was added. Taking into account that other vasoactive drugs could also improve tumor response to ILP, we evaluated histamine (Hi) as an alternative to TNF-alpha.

Methods: We used a rat ILP model to assess the combined effects of Hi and melphalan (n = 6) on tumor regression, melphalan uptake (n = 6), and tissue histology (n = 2) compared with Hi or melphalan alone.

Human red blood cells: rheological aspects, uptake, and release of cytotoxic drugs.

The shape of a normal human red blood cell (RBC) is well known: under resting conditions it is that of a biconcave discocyte. However, RBCs can easily undergo transformation to other shapes with stomatocytes and echinocytes as extremes. Various anticancer agents, generally reactive and labile substances, e.

Isolated hypoxic hepatic perfusion with orthograde or retrograde flow in patients with irresectable liver metastases using percutaneous balloon catheter techniques: a phase I and II study.

Background: Isolated hepatic perfusion for irresectable metastases confined to the liver has reported response rates of 50% to 75%. Magnitude, costs, and nonrepeatability of the procedure are its major drawbacks. We developed a less invasive, less costly, and potentially repeatable balloon catheter-mediated isolated hypoxic hepatic perfusion (IHHP) technique.

Quantification of the anticancer agent STI-571 in erythrocytes and plasma by measurement of sediment technology and liquid chromatography-tandem mass spectrometry.

An isocratic high-performance liquid chromatographic method coupled to tandem mass spectrometry for the quantification of the revolutionary and promising anticancer agent STI-571 (tradenames Gleevec, Glivec, Imatinib) in blood plasma and red blood cells (RBCs) is described. The method involves measurement of sediment technology for RBCs and a subsequent single protein precipitation step by the addition of acetonitrile to both the RBC isolate and plasma. The sample mixture was centrifuged (10 min, 3600 g), and the supernatant filtered through a HPLC filter (0.

Pharmacokinetics after pulmonary artery perfusion with gemcitabine.

Background: Isolated lung perfusion (ILuP) proved to be superior for the treatment of lung metastases compared with intravenous (i.v.) injection.

Isolated lung perfusion with gemcitabine in a rat: pharmacokinetics and survival.

Background: Toxicity and pharmacokinetics of gemcitabine (GCB) were evaluated in a rat model of isolated lung perfusion (ILuP) and compared to intravenous (iv) infusion.

Materials And Methods: CC531S adenocarcinoma cells were incubated in vitro for 24 h with GCB. Cell survival was determined 4 days after GCB treatment with the sulforhodamine B test.

Oxidative DNA damage: biological significance and methods of analysis.

All forms of aerobic life are subjected constantly to oxidant pressure from molecular oxygen and also reactive oxygen species (ROS), produced during the biochemical utilization of O2 and prooxidant stimulation of O2 metabolism. ROS are thought to influence the development of human cancer and more than 50 other human diseases. To prevent oxidative DNA damage (protection) or to reverse damage, thereby preventing mutagenesis and cancer (repair), the aerobic cell possesses antioxidant defense systems and DNA repair mechanisms.