Role of Seroalbumin in the Cytotoxicity of cis-Dichloro Pt(II) Complexes with (N

Given the potent anticancer properties of cis-diamminedichloroplatinum(II) and knowing its mode of action, we synthesized four new cis-[PtCl2(N^N)] organoplatinum complexes, two with N-substituted pbi ligands (pbiR = 1-R-2-(2-pyridyl)benzimidazole) (namely, 1 and 2) and two more with 4,4'-disubstituted bpy ligands (bpy = 2,2'-bipyridine) (namely, 3 and 4). We explored their cytotoxicity and ability to bind to deoxyguanosine monophosphate (dGMP), DNA, and albumin models. By 1H NMR and UV-vis spectroscopies, circular dichroism, agarose gel electrophoresis, differential scanning calorimetry measurements, and density functional theory calculations, we verified that only 3 can form aquacomplex species after dimethyl sulfoxide solvation; surprisingly, 1, 2, and 3 can bind covalently to DNA, whereas 4 can form a noncovalent complex. Interestingly, only complexes 1 and 4 exhibit good cytotoxicity against human ovarian carcinoma (HeLa) cell line, whereas 2 and 3 are inactive. Although lung carcinoma (A549) cells are more resistant to the four platinum complexes than HeLa cells, when the protein concentration in the extracellular media is lower, the cytotoxicity becomes substantially enhanced. By native electrophoresis of bovine seroalbumin (BSA) and inductively coupled plasma mass spectrometry uptake studies we bear out, on one hand, that 2 and 3 can interact strongly with BSA and its cellular uptake is negligible and, on the other hand, that 1 and 4 can interact with BSA only weakly, its cellular uptake being higher by several orders. These results point up the important role of the protein binding features on their biological activity and cellular uptake of cis-"PtCl2" derivatives. Our results are valuable in the future rational design of new platinum complexes with improved biological properties, as they expose the importance not only of their DNA binding abilities but also of additional factors such as protein binding.

Inferring the skeleton cell cycle regulatory network of malaria parasite using comparative genomic and variational Bayesian approaches.

The development of new antimalarial drugs is urgently needed due to elevated drug resistance in the causative agents Plasmodium parasites. An intervention strategy based on the interruption of the parasite cell cycle could be undertaken using a systems-biology aided drug discovery approach. However, little is known about the components or the mechanism of parasite cell cycle control to date. In this proof of concept study, we attempted to infer the skeleton components using comparative genomic analysis and to uncover the genetic regulatory network (GRN) ab initio using a Variational Bayesian expectation maximization (VBEM) approach.

Characterization of electron contamination in megavoltage photon beams.

The purpose of the present study is to characterize electron contamination in photon beams in different clinical situations. Variations with field size, beam modifier (tray, shaping block) and source-surface distance (SSD) were studied. Percentage depth dose measurements with and without a purging magnet and replacing the air by helium were performed to identify the two electron sources that are clearly differentiated: air and treatment head. Previous analytical methods were used to fit the measured data, exploring the validity of these models. Electrons generated in the treatment head are more energetic and more important for larger field sizes, shorter SSD, and greater depths. This difference is much more noticeable for the 18 MV beam than for the 6 MV beam. If a tray is used as beam modifier, electron contamination increases, but the energy of these electrons is similar to that of electrons coming from the treatment head. Electron contamination could be fitted to a modified exponential curve. For machine modeling in a treatment planning system, setting SSD at 90 cm for input data could reduce errors for most isocentric treatments, because they will be delivered for SSD ranging from 80 to 100 cm. For very small field sizes, air-generated electrons must be considered independently, because of their different energetic spectrum and dosimetric influence.

Comparison between TG-51 and TRS-398: electron contamination effect on photon beam-quality specification.

Two dosimetry protocols based on absorbed dose to water have recently been implemented: TG-51 and TRS-398. These protocols use different beam-quality indices: %dd(10)x and TPR20,10. The effect of electron contamination in measurements of %dd(10)x has been proposed as a disadvantage of the TG-51. For actual measurements of %dd(10)x in five clinical beams (Primus 6-18 MV, SL-75/5 6 MV, SL-18 6-15 MV) a purging magnet was employed to remove the electron contamination. Also, %dd(10)x was measured in the different ways described in TG-51 for high-energy beams: with a lead foil at 50 cm from the phantom surface, at 30 cm, and for open beam. Moreover, TPR20,10 was determined. Also, periodic quality-control measurements were used for comparing both quality indices and variation over time, but D20,10 was used instead of TPR20,10 and measurements in open beam for the %dd(10)x determination. Considering both protocols, S(w,air) and kQ were calculated in order to compare the results with the experimental data. Significant differences (0.3% for kQ) were only found for the two high-energy beams, but when the electron contamination is underestimated by TG-51, the difference in kQ is lower. Differences in the other cases and variations over time were less than 0.1%.