Saleh Altuwaijri

NF-κB Regulates Androgen Receptor Expression and Prostate Cancer Growth

Prostate cancers that progress during androgen-deprivation therapy often overexpress the androgen receptor (AR) and depend on AR signaling for growth. In most cases, increased AR expression occurs without gene amplification and may be due to altered transcriptional regulation. The transcription factor nuclear factor (NF)-kappaB, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways. NF-kappaB is an important determinant of prostate cancer clinical biology, and therefore we investigated its role in the regulation of AR expression. We found that NF-kappaB expression in prostate cancer cells significantly increased AR mRNA and protein levels, AR transactivation activity, serum prostate-specific antigen levels, and cell proliferation. NF-kappaB inhibitors decrease AR expression levels, prostate-specific antigen secretion, and proliferation of prostate cancer cells in vitro. Furthermore, inhibitors of NF-kappaB demonstrated anti-tumor activity in androgen deprivation-resistant prostate cancer xenografts. In addition, levels of both NF-kappaB and AR were strongly correlated in human prostate cancer. Our data suggest that NF-kappaB can regulate AR expression in prostate cancer and that NF-kappaB inhibitors may have therapeutic potential.

Tangential beam IMRT versus tangential beam 3D-CRT of the chest wall in postmastectomy breast cancer patients: A dosimetric comparison

BackgroundThis study evaluates the dose distribution of reversed planned tangential beam intensity modulated radiotherapy (IMRT) compared to standard wedged tangential beam three-dimensionally planned conformal radiotherapy (3D-CRT) of the chest wall in unselected postmastectomy breast cancer patientsMethodsFor 20 unselected subsequent postmastectomy breast cancer patients tangential beam IMRT and tangential beam 3D-CRT plans were generated for the radiotherapy of the chest wall. The prescribed dose was 50 Gy in 25 fractions. Dose-volume histograms were evaluated for the PTV and organs at risk. Parameters of the dose distribution were compared using the Wilcoxon matched pairs test.ResultsTangential beam IMRT statistically significantly reduced the ipsilateral mean lung dose by an average of 21% (1129 cGy versus 1437 cGy). In all patients treated on the left side, the heart volume encompassed by the 70% isodose line (V70%; 35 Gy) was reduced by an average of 43% (5.7% versus 10.6%), and the mean heart dose by an average of 20% (704 cGy versus 877 cGy). The PTV showed a significantly better conformity index with IMRT; the homogeneity index was not significantly different.ConclusionsTangential beam IMRT significantly reduced the dose-volume of the ipsilateral lung and heart in unselected postmastectomy breast cancer patients.

The synthesis, spectroscopic characterization and anticancer activity of new mono and binuclear phosphanegold(I) dithiocarbamate complexes

A new series of mononuclear [t-Bu3PAuS2CN(C7H7)2] (1), and binuclear [(DPPM)Au2(S2CN(CH3)2)2] (2), [(DPPM)Au2(S2CN(C2H5)2)2] (3) and [(DPPM)Au2(S2CN(C7H7)2)2] (4) [where DPPM = 1,1-bis(diphenylphosphino)methane, S2CN(CH3)2 = dimethyldithiocarbamate, S2CN(C2H5)2 = diethyldithiocarbamate and S2CN(C7H7)2 = dibenzyldithiocarbamate] gold(I) complexes have been prepared by reacting gold(I) precursors and dialkyl–diaryl dithiocarbamate ligands. The complexes were characterized by an analytical technique and spectroscopic methods such as CHNS analysis, FTIR spectroscopy; 1H, 13C and 31P NMR measurements. The molecular structure of the [t-Bu3PAuS2CN(C7H7)2] (1) complex was determined by X-ray diffraction. The gold(I) complexes (2 and 3) were found particularly to be better potent in vitro cytotoxic agents in comparison to cisplatin against HeLa, HCT15 and A549 cancer cell lines. These metal complexes could serve as attractive anticancer agents for the development of novel therapeutic strategies and to treat cervix, lung and colon cancers.

Synthesis, characterization and anti proliferative effect of [Au(en)2]Cl3 and [Au(N-propyl-en)2]Cl3 on human cancer cell lines

Two Au(III) complexes of the type [Au(en)2]Cl3 (2a) and [Au(N-pr-en)2]Cl3 (3a) were synthesized by reacting Auric acid (HAuCl(4)·3H2O) with 2 equiv. ethylenediamine (en) or N-alkyl substituted ethylenediamine ligands. This metallodrug was characterized by various analytical and spectroscopic techniques such as elemental analysis, UV-Vis, Far-IR, 1H NMR and solution 13C as well as solid 13C and 15N NMR. Potentiality of [Au(en)2]Cl3 and [Au(N-pr-en)2]Cl3 as an anti-cancer agent were investigated by measuring some relevant physicochemical and biochemical properties such as stability of Au-N bonds by vibrational stretching from Far IR as well as cytotoxicity and stomach cancer cell inhibiting effect, respectively. The solid-state 15N NMR chemical shift shows that the ligand is strongly bound to gold(III) centre via N atoms. The computational study of 2a shows that the gold coordination sphere adopts distorted square planar geometry with bidentate ethylenediamine ligands acting as a tetradentate chelate. While stable in the solution state, the in vitro biological studies performed with these compounds 2a in solution showed higher activity towards the inhibitory effects of the human cancer cell lines such as prostate cancer (PC-3) and gastric carcinoma (SGC-7901) than that of the N-substituted gold(III) complex (3a). Cytotoxicity of the new compounds has also been estimated in PC-3 and SGC-7901 cells.

Synthesis, spectroscopic characterization, electrochemical behavior and computational analysis of mixed diamine ligand gold(III) complexes: antiproliferative and in vitro cytotoxic evaluations against human cancer cell lines

The gold(III) complexes of the type [(DACH)Au(en)]Cl3, 1,2-Diaminocyclohexane ethylenediamine gold(III) chloride [where 1,2-DACHxa0=xa0cis-, trans-1,2- and S,S-1,2diaminocyclohexane and enxa0=xa0ethylenediamine] have been synthesized and characterized using various analytical and spectroscopic techniques including elemental analysis, UV–Vis and FTIR spectra; and solution as well as solid-state NMR measurements. The solid-state 13C NMR shows that 1,2-diaminocyclohexane (1,2-DACH) and ethylenediamine (en) are strongly bound to the gold(III) center via N donor atoms. The stability of the mixed diamine ligand gold(III) was determined by 1H and 13C NMR spectra. Their electrochemical behavior was studied by cyclic voltammetry. The structural details and relative stabilities of the four possible isomers of the complexes were also reported at the B3LYP/LANL2DZ level of theory. The coordination sphere of these complexes around gold(III) center adopts distorted square planar geometry. The computational study also demonstrates that trans- conformations is slightly more stable than the cis-conformations. The antiproliferative effects and cytotoxic properties of the mixed diamine ligand gold(III) complexes were evaluated in vitro on human gastric SGC7901 and prostate PC3 cancer cells using MTT assay. The antiproliferative study of the gold(III) complexes on PC3 and SGC7901 cells indicate that complex 1 is the most effective antiproliferative agent among mixed ligand based gold(III) complexes 1–3. The IC50 data reveal that the in vitro cytotoxicity of complexes 1 and 3 against SGC7901 cancer cells are fairly better than that of cisplatin.

Impact of the frequency of online verifications on the patient set-up accuracy and set-up margins

PurposeThe purpose of the study was to evaluate the patient set-up error of different anatomical sites, to estimate the effect of different frequencies of online verifications on the patient set-up accuracy, and to calculate margins to accommodate for the patient set-up error (ICRU set-up margin, SM).Methods and materialsAlignment data of 148 patients treated with inversed planned intensity modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) of the head and neck (n = 31), chest (n = 72), abdomen (n = 15), and pelvis (n = 30) were evaluated. The patient set-up accuracy was assessed using orthogonal megavoltage electronic portal images of 2328 fractions of 173 planning target volumes (PTV). In 25 patients, two PTVs were analyzed where the PTVs were located in different anatomical sites and treated in two different radiotherapy courses. The patient set-up error and the corresponding SM were retrospectively determined assuming no online verification, online verification once a week and online verification every other day.ResultsThe SM could be effectively reduced with increasing frequency of online verifications. However, a significant frequency of relevant set-up errors remained even after online verification every other day. For example, residual set-up errors larger than 5 mm were observed on average in 18% to 27% of all fractions of patients treated in the chest, abdomen and pelvis, and in 10% of fractions of patients treated in the head and neck after online verification every other day.ConclusionIn patients where high set-up accuracy is desired, daily online verification is highly recommended.

Synthesis, spectroscopic characterization, X-ray structure and electrochemistry of new bis(1,2-diaminocyclohexane)gold(III) chloride compounds and their anticancer activities against PC3 and SGC7901 cancer cell lines

New gold(III) compounds with chemical formulae [Au{cis-(1,2-DACH)}2]Cl31, [Au{trans-(±)-(1,2-DACH)}2]Cl32 and [Au{(S,S)-(+)-1,2-(DACH)}2]Cl33 (where 1,2-DACH = 1,2-diaminocyclohexane) have been synthesized. The synthesized compounds were characterized using elemental analysis, various spectroscopic techniques including UV-vis, FTIR spectroscopy, solution and solid-state NMR measurements; and X-ray crystallography. The stability of compounds 1, 2 and 3 was checked by UV-vis spectroscopy and NMR measurements. The electrochemical behavior was also investigated through cyclic voltammetry. The potential of the three compounds as anticancer agents was investigated by measuring in vitro cytotoxicity in terms of IC50 and inhibitory effects on growth of human prostate (PC3) and gastric (SGC7901) cancer cell lines. [Au{trans-(±)-(1,2-DACH)}2]Cl3 (2) showed a better in vitro inhibitory effect on growth of human prostate (PC3) and gastric (SGC7901) cancer cell lines than [Au{cis-(1,2-DACH)}2]Cl3 (1) and [Au{(S,S)-(+)-(1,2-DACH)}2]Cl3 (3).

Synthesis, characterization and theoretical calculations of (1,2-diaminocyclohexane)(1,3-diaminopropane)gold(III) chloride complexes: in vitro cytotoxic evaluations against human cancer cell lines

The gold(III) complexes of the type (1,2-diaminocyclohexane)(1,3-diaminopropane)gold(III) chloride, [(DACH)Au(pn)]Cl3, [where DACHxa0=xa0cis-, trans-1,2- and S,S-1,2-diaminocyclohexane and pnxa0=xa01,3-diaminopropane] have been synthesized and characterized using various spectroscopic and analytical techniques including elemental analysis, UV–Vis and FTIR spectroscopy; solution as well as solid-state NMR measurements. The solid-state 13C NMR shows that 1,2-diaminocyclohexane (1,2-DACH) and 1,3-diaminopropane (pn) are strongly bound to the gold(III) center via N donor atoms. The stability of the mixed diamine ligand gold(III) was checked by UV–Vis spectroscopy and NMR measurements. The molecular structure of compound 1 (containing cis-1,2-DACH) was determined by X-ray diffraction analysis. The structure of 1 consists of [(cis-DACH)Au(pn)]3+ complex ion and chloride counter ions. Each gold atom in the complex ion adopts a distorted square-planar geometry. The structural details and relative stabilities of the four possible isomers of the complexes were also estimated at the B3LYP/LANL2DZ level of theoretical calculations. The computational study demonstrates that trans- conformations are slightly more stable than the cis- conformations. The antiproliferative effects and cytotoxic properties of the mixed ligand gold(III) complexes were evaluated in vitro on human gastric SGC7901 and prostate PC3 cancer cells using MTT assay. The antiproliferative study of the gold(III) complexes on PC3 and SGC7901 cells indicate that complex 3 (containing 1S,2S-(+)-1,2-(DACH)) is the most effective antiproliferative agent. The IC50 data reveal that the in vitro cytotoxicity of complex 3 against SGC7901 cancer cells manifested similar and very pronounced cytotoxic effects with respect to cisplatin. Moreover, the electrochemical behavior, and the interaction of complex 3 with two well-known model proteins, namely, hen egg white lysozyme and bovine serum albumin is also reported.

In vivo surface dose measurement using GafChromic film dosimetry in breast cancer radiotherapy: comparison of 7-field IMRT, tangential IMRT and tangential 3D-CRT

PurposeThe purpose of this study was to compare the surface dose of 7-field IMRT (7xa0F-IMRT), tangential beam IMRT (TB-IMRT), and tangential beam 3D-CRT (3D-CRT) of breast cancer patients receiving adjuvant radiotherapy by means of in vivo GafChromic film dosimetry.Material and methodsBreast cancer patients receiving adjuvant radiotherapy of the whole breast or the chest wall were eligible for the study. Study patients were treated with a treatment plan using two different radiotherapy techniques (first patient series, 3D-CRT followed by TB-IMRT; second patient series, TB-IMRT followed by 7xa0F-IMRT). The surface dose was evaluated on three consecutive treatment fractions per radiotherapy technique using in vivo GafChromic film dosimetry. The paired t-test was used to assess the difference of in vivo GafChromic film readings or calculated plan parameters of the compared pairs of radiation techniques for statistical significance.ResultsForty-five unselected breast cancer patients were analysed in this study. 7xa0F-IMRT significantly reduced the surface dose compared to TB-IMRT. Differences were greatest in the central and lateral breast or chest wall region and amounted to a dose reduction of -11.8% to -18.8%. No significant difference of the surface dose was observed between TB-IMRT and 3D-CRT. A corresponding observation was obtained for the calculated skin dose derived from dose-volume histograms.ConclusionsIn adjuvant breast cancer radiotherapy, 7xa0F-IMRT offers a significantly reduced surface dose compared to TB-IMRT or 3D-CRT.

Identification of breast cancer patients with a high risk of developing brain metastases: a single-institutional retrospective analysis

BackgroundThe objective of this study was to identify breast cancer patients with a high risk of developing brain metastases who may benefit from pre-emptive medical intervention.MethodsMedical records of 352 breast cancer patients with local or locoregional disease at diagnosis were retrospectively analysed. The brain metastasis-free survival was estimated using the Kaplan-Meier method and patient groups were compared using the log rank test. The simultaneous relationship of multiple prognostic factors was assessed using Cox’s proportional hazard regression analysis. The Fisher exact test was used to test the difference of proportions for statistical significance.ResultsOn univariate analysis, statistically highly significant unfavourable risk factors for the brain metastasis-free survival were negative ER status, negative PR status, and triple negative tumor subtype. Young age at diagnosis (≤35xa0years) and advanced disease stage were not statistically significant (pu2009=u20090.10). On multivariate analysis, the only independent significant factor was the ER status (negative ER status; hazard radio (95% confidence interval), 5.1 (1.8-14.6); pu2009=u20090.003). In the subgroup of 168 patients with a minimum follow-up of 24xa0months, 49 patients developed extracranial metastases as first metastatic event. Of those, 7 of 15 (46.6%) with a negative ER status developed brain metastases compared to 5 of 34 (14.7%) with a positive ER status (Fisher exact test, pu2009=u20090.03). The median time interval (minimum-maximum) between the diagnosis of extracranial and brain metastases was 7.5xa0months (1-30 months).ConclusionsBreast cancer patients with extracranial metastasis and negative ER status exhibited an almost 50% risk of developing brain metastasis during their course of disease. Future studies are highly desired to evaluate the efficacy of pre-emptive medical intervention such as prophylactic treatment or diagnostic screening for high risk breast cancer patients.