Synthesis of Novel Structural Hybrids between Aza-Heterocycles and Azelaic Acid Moiety with a Specific Activity on Osteosarcoma Cells.

Nine compounds bearing pyridinyl (or piperidinyl, benzimidazolyl, benzotriazolyl) groups bound to an azelayl moiety through an amide bond were synthesized. The structural analogy with some histone deacetylase inhibitors inspired their syntheses, seeking new selective histone deacetylase inhibitors (HDACi). The azelayl moiety recalls part of 9-hydroxystearic acid, a cellular lipid showing antiproliferative activity toward cancer cells with HDAC as a molecular target. Azelayl derivatives bound to a benzothiazolyl moiety further proved to be active as HDACi. The novel compounds were tested on a panel of both normal and tumor cell lines. Non-specific induction of cytotoxicity was observed in the normal cell line, while three of them induced a biological effect only on the osteosarcoma (U2OS) cell line. One of them induced a change in nuclear shape and size. Cell-cycle alterations are associated with post-transcriptional modification of both H2/H3 and H4 histones. In line with recent studies, revealing unexpected HDAC7 function in osteoclasts, molecular docking studies on the active molecules predicted their proneness to interact with HDAC7. By reducing side effects associated with the action of the first-generation inhibitors, the herein reported compounds, thus, sound promising as selective HDACi.

Indole Derivative Interacts with Estrogen Receptor Beta and Inhibits Human Ovarian Cancer Cell Growth.

Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERß) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERß expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re-expression by genetic engineering, as well as the use of targeted ERß therapies, still constitute an important therapeutic approach. 3-{[2-chloro-1-(4-chlorobenzyl)-5-methoxy-6-methyl-1H-indol-3-yl]methylene}-5-hydroxy-6-methyl-1,3-dihydro-2H-indol-2-one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and liquid chromatography mass spectrometry were exploited to localize and quantify compound 3 in cells. Molecular docking was used to prove compound 3 binding to ERß. Mass spectrometry-based approaches were used to analyze histone post-translational modifications. Finally, gene expression analyses revealed a set of genes regulated by the ERß/3 complex, namely CCND1, MYC, CDKN2A, and ESR2, providing possible molecular mechanisms that underline the observed antiproliferative effects.

Serum albumin-bound proteomic signature for early detection and staging of hepatocarcinoma: sample variability and data classification.

BACKGROUND: Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) proteomic signature might be of interest for the early detection and staging of hepatocellular carcinoma (HCC). However, published procedures have been criticized for the lack of data about analytical reproducibility, and the use of inadequate data processing. METHODS: MALDI-TOF profiling of peptides bound to serum albumin ("albuminome") was performed using 90 µL of serum from 45 study subjects (HCV-related cirrhosis, small, unifocal HCCs and advanced HCCs). To overcome the large intra-sample variability, a Quality Assurance protocol was implemented, and 4-8 samples for each subject were processed and analyzed. Overall, 522 subject samples and 299 quality-control spectra were analyzed. A machine-learning approach (Random Forest) was applied to analyze the data sets. RESULTS: Mean intra-sample coefficient of variation (CV) of the analytical procedure was 17.6%-30.0%; inter-subject CV was in the range 48.8%-71.3% among the three study groups. The Random Forest procedure correctly classified 433/522 "patient samples" and 295/299 "reference samples"; 43/45 patients were correctly classified following this approach. CONCLUSIONS: Our data suggest that, notwithstanding the large analytical variability found, multiple proteomic profiles obtained from each subject can differentiate cirrhosis with and without HCC, and HCCs with and without vascular invasion, warranting further investigation in a prospective setting.

Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group.

PURPOSE: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 micromol/L (t(C > 0.05-0.2)) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. EXPERIMENTAL DESIGN: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m(2)) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. RESULTS: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel t(C > 0.05) was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel t(C > 0.05) > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel t(C > 0.05) < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel t(C > 0.05) was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (C(max) and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10(-4)). CONCLUSIONS: In this group of patients, paclitaxel t(C > 0.05) is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

[Accessibility of home palliative care and place of death of cancer patients: data analysis of the Emilia-Romagna Region.] / Accessibilità di cure palliative domiciliari e luogo del decesso dei malati oncologici: analisi dei dati della Regione Emilia-Romagna.

INTRODUCTION: The ANT Foundation is one of the main non-profit organizations providing palliative care in Italy. For more than 30 years, it has developed a comprehensive home palliative care program for cancer patients predominately active in the Bologna province. One of its main achievements has allowed for the majority of patients to be assisted at home during the last weeks of their lives until time of death. The purpose of the present study is to evaluate the possible impact of the ANT program on health data relating to the location of where cancer patients die within the Local Health Care system area (AUSL) of Bologna, compared to what happens in the other AUSLs of the Emilia-Romagna Region (ERR) where it is not present. METHODS: Regional cancer mortality data in 2005, 2010 and 2015, according to place of death and AUSL, were obtained by consulting the RER database. Data on patients assisted in the same time periods by the ANT program in the Bologna AUSL area were extracted from the ANT Foundation database and analyzed for place of death. RESULTS: In the year 2015, 2965 cancer patients died in the Bologna AUSL area. Compared to other AUSL areas of the ERR, it presents with a lower hospital mortality rate (31.2% vs. 47.5%) and a higher home mortality rate (32.8% vs. 19.6%). On the other hand, in 2015 the ANT program had assisted almost 50% of the total number of cancer patients who died in the Bologna AUSL area. Out of these patients, 64.6% died at home, while only 18.7% and 16.6% died in hospital and hospice, respectively. Conversely, hospital and home mortality rates in patients of the Bologna AUSL area who were not assisted by the ANT program, did approximate the mean values of the other ERR AUSLs. Over the 2005-2015 time span, the home mortality rate in the ANT patient series remained about twice as high as those of the Bologna AUSL. CONCLUSIONS: The comprehensive home palliative care program of the ANT Foundation seems to have a strong impact in determining the reduced hospital mortality rate of the Bologna AUSL area when compared to the other AUSLs of the Emilia-Romagna Region. The extension of this model of comprehensive home-based palliative care to other areas could contribute to reduce the high hospital mortality rate of cancer patients in this Italian Region.

Quinone-Fused Pyrazoles through 1,3-Dipolar Cycloadditions: Synthesis of Tricyclic Scaffolds and in vitro Cytotoxic Activity Evaluation on Glioblastoma Cancer Cells.

A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2 CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5 µm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.

Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG.

AIMS: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients. PATIENTS AND METHODS: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response. RESULTS: Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 micromol . h/L [95% CI 889, 1001] vs 602 micromol . h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance. CONCLUSIONS: The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group.

High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia: a pharmacokinetic and clinical study.

OBJECTIVE: High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an efficient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic efficacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal fluid (CSF) of patients treated with HD-IDA. PATIENTS AND METHODS: Twenty-five patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m2 from days 1-5, idarubicin (HD-IDA) 40 mg/m2 as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 microg/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15 patients at different times. IDA and IDAol concentrations were quantified by a validated HPLC assay described in detail elsewhere. RESULTS: Eleven patients (44%, 95% CI: 23-65%) achieved complete remission with median disease free survival for 6 months. After administration of HD-IDA i.v. bolus of 40 mg/m2, plasma level profiles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients (14.9 h) was not significantly different from the mean value observed after standard dose (13.9 h, P=0.72). IDAol t1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P=0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are significantly higher than those observed in patients treated with 12 mg/m2 of IDA but, although the administered dose (mg/m2) of the drug is 3.3 times higher, IDA exposure (measured in terms of AUC) is only 2.3 times and IDAol exposition 2.1 times greater. Furthermore, HD infusion resulted in a ratio between the AUC of parent drug and idarubicinol not different from the value observed with the standard-dose. IDA and IDAol were measurable only in 3 of the 15 cerebrospinal fluid samples collected. CONCLUSION: Responses observed in our series are comparable to those reported with other salvage regimens. The IDA exposure lower than expected may explain the safety of the single i.v. administration of 40 mg/m2 of IDA, combined with HD Ara-C, with a degree of myelosuppression equivalent to that reported with this agent administered in standard doses. Our data do not allow us to clearly attribute this behavior to a pharmacokinetic non-linearity since the baseline creatinine clearance, even within normal values, and patient age are significantly different in the two groups. Cerebrospinal fluid penetration was poor, reaching levels not considered as cytotoxic.

Impact of intervention aimed at improving the integration of oncology units and local palliative care services: results of the multicentre prospective sequential MIRTO study.

BACKGROUND: Chemotherapy (CT) in patients with advanced cancer (ACP) near the end of life is an increasing practice of oncology units. A closer integration with palliative care (PC) services could reduce the use of potentially harmful CT. This prospective study is aimed at assessing whether a more integrated care model could reduce CT use near the end of life and increase local PC service utilisation. METHODS: The study enrolled sequentially two cohorts of ACP with an estimated life expectancy of ≤6 months. In the first cohort, the usual oncologist's practice to prescribe CT and to activate local PC services were recorded. In cohort 2, the oncologist's decision was taken after an in-hospital consultation with the local PC teams. After patient death, a follow-back survey was carried out. RESULTS: The two cohorts included 109 and 125 evaluable patients, respectively. The oncologist's decision to prescribe CT occurred in 51.4% and 60%, respectively: the percentages of patients receiving the final CT administration in the last 30 days of life did not differ in the two cohorts (33.9% and 29.3%, respectively,p=0.83). Conversely, an increase in home PC service utilisation (from 56.9% to 82.4%, p=0.00), at home deaths (from 40.4% to 56.8%, p=0.01) and in-hospice deaths (from 8.3% to 19.2%, p=0.00) occurred in cohort 2. CONCLUSION: The implementation of an initial in-hospital consultation of oncologists and experienced home PC teams has not reduced the use of CT near the end of life but increased PC service utilisation and reduced in-hospital deaths.

Design, synthesis and biological evaluation of pyrazole derivatives as potential multi-kinase inhibitors in hepatocellular carcinoma.

We described the optimization, by molecular modelling, of small pyrazole derivatives, as kinase inhibitors, obtained through a 1,3-dipolar cycloaddition between nitrile imines and functionalized acetylenes. The two compounds, selected as potential agents active against hepatocellular carcinoma (HCC) were then evaluated in vitro for their biological activity on HCC-derived cell lines. The compounds show a promising inhibitory growth efficacy (IC(50) 50-100 µM) in SNU449 cell line, as well as block of cell cycle progression and induction of apoptosis, and can be considered as lead compounds for further SAR developments.

Design and synthesis of novel 3,4-disubstituted pyrazoles for nanomedicine applications against malignant gliomas.

A series of novel 3,4-disubstituted pyrazoles were synthesized. The cytotoxicity against U87MG glioma cell line have been investigated in vitro and three of these compounds showed promising inhibitory activity on cell growth with an IC50 lower than 90 microM. AutoDock molecular docking into type I TGF-beta receptor (TGF-beta-RI; PDB: 1py5) has been done for lead optimization of the mentioned compounds as potential TGF-beta-RI1 inhibitors. In particular, 3-aryl-4-amido pyrazole containing long omega-amino-aliphatic chain emerged as a good candidate for further optimization. Entrapment into targetable PEG-based micelles improved growth inhibition IC50 values up to 100 nM and this could lead to a novel drug delivery strategy for treating glioblastoma.