Szabolcs Modok

Transport kinetics of four- and six-coordinate platinum compounds in the multicell layer tumour model

Four-coordinate (Pt(II)) platinum-based anticancer drugs are widely used in primary or palliative chemotherapy and produce considerable efficacy in certain clinical applications, for example testicular cancer. However, in many cancers the Pt(II) drugs are beset by poor efficacy mainly due to suboptimal pharmacokinetic properties. Consequently, the six-coordinate (Pt(IV)) class of Pt drugs were developed to improve platinum efficacy by (i) increasing stability, (ii) reducing reactivity, (iii) increasing lipophilicity, and (iv) nuclear targeting. However, comparatively little information is available on the pharmacokinetic properties of these compounds within solid tumour tissue. In the present study, the distribution and fluxes of [14C]-labelled [PtCl2(en)] (where en stands for ethane-1,2-diamine) and cis,trans-[PtCl2(OH)2(en)] drugs were determined in the multicell layer (MCL) tumour model comprising colon cancer cells. Flux data were analysed by mathematical modelling of drug diffusion and cellular uptake in the transport system. The flux of the Pt(IV) compound through the MCL was not significantly different to that of the Pt(II) drug nor were the diffusion coefficient or tissue uptake; the latter confirmed with elemental imaging analysis by synchrotron radiation induced X-ray emission. However, the flux of the Pt(IV) through the MCL was increased by hydrostatic pressure, thereby demonstrating the potential to target cancer cells further away from the vessels with six-coordinate platinum drugs.

Cytosolic Region of TM6 in P-Glycoprotein : Topographical Analysis and Functional Perturbation by Site Directed Labeling

Reduced intracellular drug accumulation due to the activity of the drug efflux pump ABC (B1) is a major mechanism in the resistance of cancer cells to chemotherapy. ABC (B1) is a poly specific transporter, and the molecular mechanism of its complex translocation process remains to be elucidated. To understand the process will require information on the regions involved in drug binding and those that couple this event to nucleotide hydrolysis. The present investigation focuses on the cytosolic region of transmembrane helix 6 (TM6), which has been widely attributed with a central role in the translocation process. A series of ABC (B1) isoforms containing a unique cysteine within TM6 was constructed and the resultant proteins purified and reconstituted. Accessibility of the cysteines to covalent modification by maleimide reagents was measured for the basal, ATP bound and vanadate trapped conformations of each isoform. Residues at the two extremes of the TM6 region examined (amino acids 344 to 360) were considerably more accessible than the central segment, the latter of which also failed to undergo significant conformational changes during the catalytic cycle. Covalent modification of the cytosolic segment of TM6 did, however, attenuate drug stimulation of ATP hydrolysis and demonstrates an important role for this segment in coupling drug binding to ATP hydrolysis during translocation.

Amyloidosis induced colonic stricture. The first symptom of myeloma multiplex. A case report

UNLABELLED Systemic amyloidosis often involves the gastrointestinal tract and usually presents as ulceration or polypoid lesions. However, annular stricture of the colon due to amyloidosis is very rare. Amyloidosis develops in appr. 10% of multiple myeloma patients with lambda light chain production, it is usually type AL and not a presenting symptom. CASE REPORT A 73-year-old female patient appeared at our hospital with anaemia, abdominal pain and hematochezia. Colonoscopy revealed a circular narrowing of the sigmoid colon suggesting malignancy. The patient underwent sigmoid resection and rectosigmoidal anastomosis was prepared to relieve mechanical obstruction. Surprisingly the histological finding from the resected specimen was amyloidosis. Subcutaneous fat tissue biopsy established the diagnosis of systemic AA amyloidosis. Immunoelectrophoresis revealed an elevated gamma-globulin fraction with IgG lambda monoclonal component, as well as a different lambda light chain. Therefore bone marrow biopsy was carried out which confirmed the diagnosis of multiple myeloma. DISCUSSION Our case is a rare example of the extraordinary tumor-mimicking colon amyloidosis that led to the diagnosis of multiple myeloma. Beside haematological treatment, strict follow-up of the colon process and reconsideration of surgical therapy or endoscopic stenting is of great importance.

Aortic stiffness is increased in patients with hypereosinophilic syndrome being in early necrotic phase

Background Persistent eosinophilia and eosinophil-mediated single- or multiple-organ damage are typical features of hypereosinophilic syndrome (HES). Theoretically, eosinophilic infiltration of the ascending aortic wall could not be excluded in HES, therefore the present study aimed to test whether HES is associated with abnormalities in aortic elastic properties. Methods The present study comprised 10 HES patients (mean age: 57.6±10.1 years, 5 males) without known cardiovascular disease, their results were compared to 19 age-, gender- and risk factor-matched controls (59.2±4.2 years, 15 males). Complete two-dimensional Doppler echocardiography with measurement of echocardiographic aortic elastic properties was performed in all HES cases and controls. Results Although neither systolic (30.6±3.4 vs. 30.1±3.6 mm, P=ns), nor diastolic (28.7±3.6 vs. 27.8±3.2 mm, P=ns) aortic diameter differed significantly between HES patients and matched controls, significantly increased aortic stiffness index (11.19±5.65 vs. 7.04±2.97, P<0.05) could be demonstrated in HES patients. Conclusions Increased aortic stiffness could be demonstrated in HES patients in their early necrotic phase.

Original ArticleCharacterization of left atrial dysfunction in hypereosinophilic syndrome – Insights from the Motion analysis of the heart and great vessels by three-dimensional speckle tracking echocardiography in pathological cases (MAGYAR-Path) StudyCaracterização da disfunção auricular esquerda na síndrome hipereosinofílica – visão da análise de movimentos do coração e dos grandes vasos por ecocardiografia tridimensional speckle tracking em casos patológicos – estudo MAGYAR-Path

Introduction The present study was designed to compare three-dimensional speckle tracking echocardiography (3DSTE)-derived left atrial (LA) volumetric, volume-based functional and strain parameters between patients with hypereosinophilic syndrome (HES) and matched controls.