FNF-12, a novel benzylidene-chromanone derivative, attenuates inflammatory response in in vitro and in vivo asthma models mediated by M2-related Th2 cytokines via MAPK and NF-kB signaling.

BACKGROUND AND AIM: This study evaluates a novel benzylidene-chromanone derivative, FNF-12, for efficacy in in vitro and in vivo asthma models. METHODS: Rat basophilic leukemia (RBL-2H3) and acute monocytic leukemia (THP-1)-derived M2 macrophages were used. Human whole blood-derived neutrophils and basophils were employed. Flow cytometry was used for studying key signalling proteins. Platelet activation factor (PAF)-induced asthma model in guinea pigs was used for in vivo studies. RESULTS: The chemical structure of FNF-12 was confirmed with proton-nuclear mass resonance (NMR) and mass spectroscopy. FNF-12 controlled degranulation in RBL-2H3 cells with an IC50 value of 123.7 nM and inhibited TNF-α release from these cells in a dose-responsive way. The compound effectively controlled the migration and elastase release in activated neutrophils. IC50 value in the FcεRI-basophil activation assay was found to be 205 nM. FNF-12 controlled the release of lipopolysaccharide (LPS)-induced interleukin-10, I-309/CCL1 and MDC/CCL22 in THP-1 derived M2 macrophages. The compound suppressed LPS-induced mitogen activated protein kinase (MAPK)-p-p38 and nuclear factor kappa B(NF-kB)-p-p65 expression in these cells. A dose-dependent decrease in the accumulation of total leucocytes, eosinophils, neutrophils and macrophages was observed in PAF-induced animal models. CONCLUSION: FNF-12 was able to control the inflammatory responses in in vitro and in vivo asthma models, which may be driven by controlling M2-related Th2 cytokines via MAPK and NF-kB signaling.

The SMAC mimetic AT-101 exhibits anti-tumor and anti-metastasis activity in lung adenocarcinoma cells by the IAPs/ caspase-dependent apoptosis and p65-NFƙB cross-talk.

OBJECTIVES: The Inhibitors of Apoptosis (IAPs) regulate initiator and effector phases of caspase mediated apoptosis. This study evaluates the effects of SMAC mimetic AT-101 in regulation of IAPs/caspases/NFƙB-p65 in an adenocarcinoma cell line. MATERIALS AND METHODS: MTT assay was performed in the NCI-H522 cell line. Flow cytometry was used for detecting cell cycle, apoptosis, and NFƙB-p65 regulation. Effects of AT-101 on IAPs and caspases were determined by quantitative real time-PCR and western blotting. AutoDock-VINA was used for computational analysis. RESULTS: AT-101 reduced the cell proliferation of NCI-H522 with a GI50 value of 7 µM. The compound arrested adenocarcinoma cells in the G1 phase of the cell cycle and increased early and late phase apoptosis while decreasing tumor-cell trans-migration. AT-101 treatment to NCI H522 at a concentration of 0.35 µM decreased XIAP, cIAP-1, and cIAP-2 mRNA levels to 4.39±0.66, 1.93±0.26, and 2.20±0.24 folds, respectively. Increased dose of AT-101 at 0.7 µM concentration further decreased XIAP, cIAP-1, and cIAP-2 mRNA levels to 2.44±0.67, 1.46±0.93, and 0.97±0.10 folds, respectively. Similar effects of a dose-dependent decrease in the protein expressions of XIAP, cIAP-1, and cIAP-2 were observed with AT-101 treatments, while a dose-responsive increase in the mRNA and protein expression levels of caspase 6 and caspase 7 was observed in the NCI-H522 cell line. The compound exhibited binding affinity (-6.1 kcal/mol) and inhibited NFƙB-p65 in these cells. CONCLUSION: AT-101 had anti-tumor efficacy against lung adenocarcinoma cells which could be mediated through IAPs/caspase-dependent apoptosis and NFƙB-p65 cross talk. Results from this study suggests a signal cross talk between IAPs and NFkB and open new channels for further investigations in therapeutic intervention against lung cancer management.

Aurone: A biologically attractive scaffold as anticancer agent.

Aurones are very simple, promising anticancer lead molecules containing three rings (A, B and C). A very slight structural variation in the aurones elicits diverse affinity and specificity towards different molecular targets. The present review discusses the design, discovery and development of natural and synthetic aurones as small molecule anticancer agents. Detailed structure-activity relationship and intermolecular interactions at different targets are also discussed. Due to their rare occurrence in nature and minimal mention in literature, the anticancer potential of aurones is rather recent but in constant progress.

Quantification of trends in radiation oncology infrastructure in Pakistan, 2004-2009.

AIM: To provide objective estimates of radiation oncology infrastructure in Pakistan for the years 2004 and 2009 in order to quantify trends in radiotherapy facilities, patient load and to identify the future needs. METHODS: Nationwide surveys using structured questionnaires were conducted in 2005 and 2010 by the Institute of Radiotherapy and Nuclear Medicine, Peshawar, to assess the status of radiation oncology infrastructure in 2004 and 2009. The data were analyzed to observe the trends. RESULTS: Megavoltage teletherapy machines increased from 37 in 2004 to 41 in 2009. New patients registered in all radiotherapy centers were 33 369 in 2004 and 46 114 in 2009. Conventional simulators used for tumour localization increased from 15 to 21 and computerized tomography simulators from 0 to 07. Radiation treatment planning systems for dose calculations of tumors and vital organs increased from 15 to 26 and brachytherapy units from 12 to 13. There were 725 patients per medical physicist in 2004 versus 632 in 2009. Patients per radiation oncologist were 439 in 2004 versus 549 in 2009. Number of radiotherapy technologists/shift/machine was 1.69 in 2004 versus 1.90 in 2009. Repair maintenance personnel improved from 2.11/2 megavoltage units in 2004 to 2.49 in 2009. CONCLUSION: While there was an increase in number of radiotherapy centers, equipment and human resources available, this was insufficient to comply with international guidelines. An adequate enhancement in radiation oncology infrastructure is needed to cope with the predicted rise in cancer incidence.

Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial.

BACKGROUND: Several large randomised studies from western Europe and the USA have shown that accelerated fractionation of radiotherapy might be beneficial in the treatment of squamous-cell carcinoma of the head and neck (HNSCC). The aim of this study--the International Atomic Energy Agency (IAEA) ACC trial--was to determine whether accelerated fractionation could be applied in developing countries, where there are fewer therapeutic resources and where tumour burdens can be heavier. METHODS: Between Jan 6, 1999, to March 31, 2004, nine centres from Asia, Europe, the Middle East, Africa, and South America recruited patients with HNSCC of the larynx, pharynx, and oral cavity who were eligible for curative radiotherapy. Patients were randomly assigned in this open-label trial to receive an accelerated regimen of six fractions of radiotherapy per week (n=458) or to receive a conventional radiotherapy regimen of five fractions per week (n=450), receiving a total dose of 66-70 Gy in 33-35 fractions. Patients were stratified by tumour localisation, T classification, histopathological grade, and institution. Randomisation was done by a central computer-generated balanced randomisation algorithm. The primary endpoint was locoregional control, analysed for all eligible patients, irrespective of whether or not they had completed the course of radiotherapy. This trial is registered with ClinicalTrials.gov, number NCT00120211. FINDINGS: Six patients in the accelerated group and two in the conventional group were excluded from analyses because of withdrawal of consent or missing data. The planned total radiotherapy dose was received by 418 (92%) of the 452 eligible patients in the accelerated radiotherapy group and 413 (92%) of the 448 patients in the conventional radiotherapy group. Median treatment time was 40 days in the accelerated group and 47 days in the conventional group. The 5-year actuarial rate of locoregional control was 42% in the accelerated group versus 30% in the conventional group (hazard ratio [HR] 0.63, 95% CI 0.49-0.83; p=0.004). Acute morbidity in the form of confluent mucositis was noted in 45 patients in the accelerated group and 22 patients in the conventional group (2.15, 1.27-3.35); severe skin reactions were noted in 87 patients in the accelerated group and 50 patients in the conventional group (1.91, 1.31-2.79). There were no significant differences in late radiation side-effects. INTERPRETATION: An accelerated schedule of radiotherapy for HNSCC was more effective than conventional fractionation, and since it does not require additional resources, might be a suitable new worldwide standard baseline treatment for radiotherapy of HNSCC. FUNDING: International Atomic Energy Agency, Coordinated Research Project (IAEA-CRP E.3.30.18), the Danish Cancer Society, the Danish Strategic Research Council, and the Lundbeck Centre for Interventional Research in Radiation Oncology (CIRRO).

Outcome of chemoradiation in treating carcinoma esophagus.

OBJECTIVE: To observe the role of chemoradiation in treating carcinoma of esophagus, its complications and outcome of disease. DESIGN: Analytical descriptive study. PLACE AND DURATION OF STUDY: Conducted at IRNUM in collaboration with Hayatabad Medical Complex (HMC), Peshawar, for one year. PATIENTS AND METHODS: A total of 47 males and 53 females with an average age of 53 +/- 13 years were inducted in this study. Patients having upper end carcinoma or esophageal surgery were excluded from this study. They were treated with radio as well as chemotherapy. Those patients who had completed radiation six months before were planned for repeat endoscopies. Response evaluation was categorized as no evidence of disease, residual disease or stricture formation simulating carcinoma. Seventy percent of endoscoped patients were disease free and 30% were having residual disease. Of these 30%, 10% were having growth while rest of the 20% showed stricture formation due to radiation. RESULTS: Out of 100 patients, 70% were palliated maximally and no evidence of disease was found on endoscopy done after 1-6 months. Only 30% came up again with dysphagia. Out of these 30%, 20% were having esophageal stricture, which on dilatation improved the quality of life. Rest of the 10% were having stricture hiding the residual disease. Giving 1-2 cycles of chemotherapy before the start of radiation reduced the disease burden and predicted response to radiation by improving dysphagia. CONCLUSION: In spite of certain complications like neutropenia, emesis and stricture formation, chemoradiation is still the best treatment option available. It is because of its safety, well-tolerability and cost effectiveness. It is equally good for patients who refuse surgery and those with advanced disease.

Recurrent rectal carcinoma treated with high dose rate intraluminal brachytherapy.

A 65 years old man with recurrent rectal cancer was treated with remote afterloading High Dose Rate Intraluminal Brachytherapy (HDRILB). After eight weeks of HDRILB there was complete regression of the tumor. Bleeding per rectum and pain in the perineum were greatly improved. He died of myocardial infarction after 41 months of treatment with HDRILB. The treated lesions were incomplete remission at the time of death. The procedure was well tolerated. The only treatment-associated toxicity was grade 2 proctitis, which was treated conservatively. HDRILB can be used as one of the treatment options in patients with recurrent rectal cancers who have undergone previous abdominal surgery and external beam irradiation, as exhibited in our limited experience.

High dose rate intraluminal brachytherapy in combination with external beam radiotherapy for palliative treatment of cancer rectum.

OBJECTIVE: To evaluate the feasibility, efficacy and toxicity of High Dose Rate Intraluminal Brachytherapy (HDRILB) in combination with External Beam Radiotherapy (EBR) used in the palliative treatment of selected patients of adenocarcinoma rectum. DESIGN: A prospective pilot study. PLACE AND DURATION OF STUDY: The study was conducted at the Institute of Radiotherapy and Nuclear Medicine (IRNUM), Peshawar. The study started in April 1996 and the patients accrual was completed in June 1997. PATIENTS AND METHODS: The patients with adenocarcinoma rectum, who refused surgery, had contraindications for surgery or had advanced and/or metastatic disease were treated with HDRILB in combination with external beam radiotherapy (EBR). The apparatus used for HDRILB was Ralstron 20B remote afterloading unit with 60Co stepping source. Indigenously designed rectal applicators were used. The EBR was delivered through Pheonix 60Co teletherapy machine (Theratron AECL). The data for symptom burden and symptomatic relief was analyzed by applying Likert's method of summated scales. RESULTS: Data was analyzed after one week and at the end of the treatment. After one week of treatment, the relief in pain and bleeding per rectum (P/R) was 97%. Excellent palliation was achieved at the end of the treatment when perineal pain and bleeding P/R were relieved in 100%, discharge P/R in 87% and tenesmus in 93% of the cases. CONCLUSION: The use of HDRILB in combination with EBR can provide quick relief of symptoms in selected patients of adenocarcinoma rectum. This combination has an excellent palliative value because of its effectiveness, acceptable toxicity and overall short treatment duration.