Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines

Gemcitabine and paclitaxel are active agents in the treatment of non-small-cell lung cancer (NSCLC). To optimize treatment drug combinations, simultaneously and 4 and 24 h intervals, were studied using DNA flow cytometry and multiple drug effect analysis in the NSCLC cell lines H460, H322 and Lewis Lung. All combinations resulted in comparable cytotoxicity, varying from additivity to antagonism (combination index: 1.0–2.6). Gemcitabine caused a S (48%) and G1 (64%) arrest at IC-50 and 10 × IC-50 concentrations, respectively. Paclitaxel induced G2/M arrest (70%) which was maximal within 24 h at 10 × IC-50. Simultaneous treatment increased S-phase arrest, while at the 24 h interval after 72 h the first drug seemed to dominate the effect. Apoptosis was more pronounced when paclitaxel preceded gemcitabine (20% for both intervals) as compared to the reverse sequence (8%, P = 0.173 for the 4 h and 12%, P = 0.051 for the 24 h time interval). In H460 cells, paclitaxel increased 2-fold the accumulation of dFdCTP, the active metabolite of gemcitabine, in contrast to H322 cells. Paclitaxel did not affect deoxycytidine kinase levels, but ribonucleotide levels increased possibly explaining the increase in dFdCTP. Paclitaxel did not affect gemcitabine incorporation into DNA, but seemed to increase incorporation into RNA. Gemcitabine almost completely inhibited DNA synthesis in both cell lines (70–89%), while paclitaxel had a minor effect and did not increase that of gemcitabine. In conclusion, various gemcitabine–paclitaxel combinations did not show sequence dependent cytotoxic effects; all combinations were not more than additive. However, since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of paclitaxel prior to gemcitabine might be favourable as compared to reversed sequences. © 2000 Cancer Research Campaig

Concentrations of VOCs and ozone in indoor environments: A case study in two Mediterranean cities during winter period

Building materials represent the largest surfaces indoors and are the major contributors of volatile organic compounds (VOCs) in the indoor environment. This study which is conducted in the frame of BUMA project (Prioritization of Building Materials Emissions), aims at assessing the human exposure to air hazards emitted by building materials. In this study, indoor and outdoor VOCs and ozone measurements from field campaigns in two Mediterranean cities (Nicosia and Athens in winter period) are presented and discussed. The field campaigns concern weekly measurements. The campaigns were conducted in four buildings in each city (1 Public building, 1 school and 2 houses) and concern weekly measurements. Passive samplers were used for collecting VOCs and ozone. Eight (8) hydrocarbons (benzene, toluene, ethylbenzene, m,p-xylene, a-pinene, o-xylene and d-limonene), five (5) carbonyl compounds (formaldehyde, acetaldehyde, proprionaldehyde, acetone and hexanaldehyde) and ozone have been measured. Additional air exchange measurements have been conducted using tracer gas techniques. Hazardous substances such as benzene, formaldehyde and acetaldehyde present indoor concentrations that range between 1.5-10.2, 5.8-43.2 and 4.5-15 μg/m3, respectively. VOC concentration data show a considerable variability due to the different indoor emission sources, ventilation rates and outdoor environment's influence. A significant contribution to indoor measured concentrations seems to come from the building materials. Ozone outdoor concentrations are reduced substantially inside, indicating relatively strong indoor ozone sinks

Calculating the energy spectra of magnetic molecules: application of real- and spin-space symmetries

The determination of the energy spectra of small spin systems as for instance given by magnetic molecules is a demanding numerical problem. In this work we review numerical approaches to diagonalize the Heisenberg Hamiltonian that employ symmetries; in particular we focus on the spin-rotational symmetry SU(2) in combination with point-group symmetries. With these methods one is able to block-diagonalize the Hamiltonian and thus to treat spin systems of unprecedented size. In addition it provides a spectroscopic labeling by irreducible representations that is helpful when interpreting transitions induced by Electron Paramagnetic Resonance (EPR), Nuclear Magnetic Resonance (NMR) or Inelastic Neutron Scattering (INS). It is our aim to provide the reader with detailed knowledge on how to set up such a diagonalization scheme.Comment: 29 pages, many figure

Clinical, quality of life, and economic value of acromegaly disease control

Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998–2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 μg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease

Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity

Platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (TP) catalyses the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate and is involved in the metabolism of fluoropyrimidines. It can also activate 5'-deoxyfluorouridine (5'DFUR) and possibly 5-fluorouracil (5FU) and Ftorafur (Ft), but inactivates trifluorothymidine (TFT). We studied the contribution of TP activity to the sensitivity for these fluoropyrimidines by modulating its activity and/or expression level in colon and lung cancer cells using a specific inhibitor of TIP (TPI) or by overproduction of TIP via stable transfection of human TP. Expression was analysed using competitive template-RT-PCR (CT-RT-PCR), Western blot and an activity assay. TP activity ranged from nondetectable to 70678 pmol h(-1) 10(-6) cells, in Colo320 and a TP overexpressing clone Colo320TPI, respectively. We found a good correlation between TIP activity and mRNA expression (r = 0.964, P <0.01) in our cell panel. To determine the role of TIP in the sensitivity to 5FU, 5'DFUR, Ft and TFT, cells were cultured with the various fluoropyrimidines with or without TPI and differences in IC50's were established. TPI modified 5'DFUR, increasing the IC50's 2.5- to 1396-fold in WiDR and Colo320TPI, respectively. 5-Fluorouracil could be modified by inhibiting TP but to a lesser extent than 5'DFUR: IC50's increased 1.9- to 14.7-fold for WiDR and Colo320TPI, respectively. There was no effect on TFT or Ft. There appears to be a threshold level of TP activity to influence the 5'DFUR and 5FU sensitivity, which is higher for 5FU. Even high levels of TP overexpression only had a moderate effect on 5FU sensitivity. (C) 2003 Cancer Research UK

A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer

Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen the therapeutic armamentarium, not including GEM, are warranted. MIA PaCa2, CFPAC-1 and Capan-1 pancreatic cancer cell lines were treated with GEM, fluouracil (5-FU), docetaxel (DCT), oxaliplatin (OXP), irinotecan (CPT-11), pemetrexed (PMX) and raltitrexed (RTX) as single agent. Pemetrexed, inducing apoptosis with IC50s under the Cmax in the three lines tested, appeared the most effective drug as single agent. Based on these results, schedule- and concentration-dependent drug interactions (assessed using the combination index) of PMX/GEM, PMX/DCT and PMX–CPT-11 were evaluated. The combinatory study clearly indicated the PMX and CPT-11 combination as the most active against pancreatic cancer. To confirm the efficacy of PMX–CPT-11 combination, we extended the study to a panel of 10 pancreatic cancer cell lines using clinically relevant concentrations (PMX 10 μM; CPT-11 1 μm). In eight of 10 lines, the PMX–CPT-11 treatment significantly reduced cell recovery and increased both the subG1 and caspase 3/7 fraction. After a 5-day wash out period, an increased fraction of subG1 and caspase3/7 persisted in PMX–CPT-11-pretreated cell lines and a significant reduction in the clonogenicity capacity was evident. Finally, in vivo, the PMX/CPT-11 combination showed the ability to inhibit xenograft tumours growth as second-line therapy after GEM treatment. The PMX and CPT-11 combination displays a strong schedule-independent synergistic cytotoxic activity against pancreatic cancer, providing experimental basis for its clinical testing as salvage chemotherapy in pancreatic cancer patients