Use Of Anticancer Agents Research Articles

The Possible Ameliorative Effect of L-Carnitine against Chlorambucil Induced Testicular Oxidative Stress in Adult Male Albino Rat

Abstract Background The upsurge in the use of anticancer agents has generated questions about the safety of these substances on normal tissues. One of these drugs is chlorambucil, which is used in the treatment of CLL (chronic lymphocytic leukemia). Recent clinical observational studies claimed that the use of L- carnitine might have a protective effect against a wide variety of testicular damage that might progress to male infertility. Aim of the Work The aim of the current work was to demonstrate the possible protective capacity of L- carnitine on the oxidative histological changes of the testes induced by chlorambucil on adult male albino rat. Material and Methods Forty adult male albino rats were assigned into four groups for experiment for 21 successive days. In the control group (I) rats were not subjected to any treatment. In group (II), rats received daily oral L-carnitine in dose of 500 mg per kg per day. In group (III), rats received chlorambucil orally by gastric tube at a dose of 0.2 mg per kg per day dissolved in distilled water. In group (IV), rats were co-administered L-carnitine and chlorambucil. Animals were then sacrificed, and testes specimens were weighted then processed into paraffin blocks, sectioned, and stained with H&E and PAS. Specimens were also processed for semithin sections. Morphometric study and statistical analysis were done. Results The histomorphology of the testes sections from chlorambucil treated groups were strongly altered by rarefaction and vacuolization in the seminiferous epithelium, germ cell exfoliation and the presence of giant cells. Further study revealed a high percentage of damaged tubules, decreased germinal epithelial height, and absence of sperms in lumina. Histological examination of testis sections from L-carnitine protected group showed a considerable amelioration of damage and vacuolations. Moreover, many sections showed normal seminiferous tubules with intact spermatogenic cells. In addition to statistically significant increase in number of damaged tubules, statistically significant decrease in weight of testis and germinal epithelial height of seminiferous tubules were found in chlorambucil treated group compared to the control group. However, statistically significant decrease in number of damaged tubules in the L- carnitine protected group was found compared to chlorambucil group. Moreover, there was significant increase in weight of testis of the L- carnitine protected group compared to chlorambucil group. Conclusion It is concluded that treatment with antioxidants such as L-carnitine protects against various tissue injuries such as chlorambucil induced testicular damage.

Efficacy of Off-Label Use of Anticancer Drugs in Oncology

The off-label use of anticancer drugs is widespread in modern oncology. The potential advantages of such prescriptions are associated with exceeding the expected clinical benefi ts over the risks of complications. The off-label use of anticancer drugs demonstrates the inconsistent efficacy of this approach depending on the type of malignancy, the reasons for prescribing these agents and their belonging to a particular pharmacological group. In a number of situations, the clinical benefits of off-label drugs are more convincing than in case of authorized indications. Currently, prescribing the “old” registered anticancer drugs, used in everyday clinical practice, is seen routine. However, labeling does not reflect the full range of indications with strong evidence of safety and efficacy. The paradigm shift toward molecularly targeted therapy and immunotherapy in various malignancies may increase the off-label use of the specified agents. Lack of treatment options for rare forms of malignancies and exhaustion of the possibilities for registered therapy are the major reasons for off-label prescribing targeted drugs based on the identifi ed molecular genetic disorders. In such cases, the concept of precision therapy is oft en implemented by using agents, the clinical efficacy of which is confi rmed by data with a low level of evidence or with no evidence. Studying the eff ectiveness of the off-label use of anticancer agents is necessary to systematize information and develop algorithms for making decisions about the prescription of these drugs in routine clinical practice.

Fluoropyrimidine usage in cases with hyperammonemia: real-world data study using the Japanese Adverse Drug Event Report (JADER) database.

Fluoropyrimidines are anticancer drugs and can cause hyperammonemia both intravenously and orally. Renal dysfunction may interact with fluoropyrimidine to cause hyperammonemia. We performed quantitative analyses of hyperammonemia using a spontaneous report database to examine the frequency of intravenously and orally administered fluoropyrimidine, the reported frequency of fluoropyrimidine-related regimens, and fluoropyrimidine's interactions with chronic kidney disease (CKD). This study used data collected between April 2004 and March 2020 from the Japanese Adverse Drug Event Report database. The reporting odds ratio (ROR) of hyperammonemia was calculated for each fluoropyrimidine drug and was adjusted for age and sex. Heatmaps depicting the use of anticancer agents in patients with hyperammonemia were drawn. The interactions between CKD and the fluoropyrimidines were also calculated. These analyses were performed using multiple logistic regression. Hyperammonemia was observed in 861 of the 641,736 adverse events reports. Fluorouracil was the most frequent drug associated with hyperammonemia (389 cases). The ROR of hyperammonemia was 32.5 (95% CI 28.3-37.2) for intravenously administered fluorouracil, 4.7 (95% CI 3.3-6.6) for orally administered capecitabine, 1.9 (95% CI 0.87-4.3) for tegafur/uracil, and 2.2 (95% CI 1.5-3.2) for orally administered tegafur/gimeracil/oteracil. Calcium levofolinate, oxaliplatin, bevacizumab, and irinotecan were the most frequently reported agents in cases of hyperammonemia with intravenously administered fluorouracil. The coefficient of the interaction term between CKD and fluoropyrimidines was 1.12 (95% CI 1.09-1.16). Hyperammonemia cases were more likely to be reported with intravenous fluorouracil than orally administered fluoropyrimidines. Fluoropyrimidines might interact with CKD in hyperammonemia cases.

Anti-tumor effects of Auraptene through induction of apoptosis and oxidative stress in a mouse model of colorectal cancer

The main strategy of cancer cells for survival is uncontrolled cell division and escape from apoptosis. The use of anticancer agents inducing the production of reactive oxygen species (ROS) and controlling cell division might be a therapeutic approach to eradicate cancer cells. Herein, we examined the therapeutic effects of Auraptene on CT26 cells as well as on a mouse model of colorectal cancer (CRC). The spheroid assay was also conducted to analyze the anti-proliferative activity of Auraptene. We also assessed the in vitro analysis of ROS generation. The impact of Auraptene on oxidant/antioxidant markers, as well as the mRNA expression of Bax, Bcl-2, Nrf2, Cyclin D1, and Survivin genes, was evaluated by qPCR in tumor samples. As a result, Auraptene significantly reduced the size of CT26 spheroids at a dose of 200 µM. After 12 h, ROS levels were significantly elevated in CT26 cells. The administration of Auraptene induced apoptosis and the cell cycle arrest by modulating Bax, Bcl-2, Nrf2, Cyclin D1, and Survivin mRNA levels. Furthermore, our results demonstrated that Auraptene suppressed CAT, GSH (reduced Glutathione), and FRAP while increasing MDA in tissue homogenates which in turn could raise oxidative stress and stimulate apoptosis. Therefore, Auraptene may act as a powerful adjuvant therapy in CRC since it triggers apoptosis and cell cycle.

A Study about the pattern of adverse effects of various oncology drugs in a Tertiary Care Hospital of North East India

The aim of the study is to observe the pattern of adverse drug reactions (ADRs) with the usage of various anti-cancer drugs in a tertiary care hospital of North East India. The study is a prospective, observational evaluation of the ADRs which was conducted over a period of 1 year. During the study period 59 cancer patients receiving chemotherapy were analysed from which a total of 79 ADRs were identified and collected which occurred during and after the cancer treatment. Maximum cases of ADR recorded in the study are mucositis, respiratory disorder, neuropathy, constipation, itching etc. On causality assessment, it was observed that nearly 92% ADRs are considered as possible, 6% are probable and 2% are unlikely. Although, the reporting of ADR is very minimal by the healthcare professionals, this study focuses on the various common ADR associated with the use of anti-cancer agents in the treatment of cancer. The information from the study might be helpful in identifying and minimizing preventable ADRs, while enhancing the knowledge of the healthcare professionals to deal with them more efficiently. Hence the study was done to record and analyze the pattern of adverse drug reaction from oncology drugs.

Generation of Human Stomach Cancer iPSC-Derived Organoids Induced by Helicobacter pylori Infection and Their Application to Gastric Cancer Research.

There is considerable cellular diversity in the human stomach, which has helped to clarify cell plasticity in normal development and tumorigenesis. Thus, the stomach is an interesting model for understanding cellular plasticity and for developing prospective anticancer therapeutic agents. However, many questions remain regarding the development of cancers in vivo and in vitro in two- or three-dimensional (2D/3D) cultures, as well as the role of Helicobacter pylori (H. p.) infection. Here, we focus on the characteristics of cancer stem cells and their derived 3D organoids in culture, including the formation of stem cell niches. We define the conditions required for such organoid culture in vitro and examine the ability of such models for testing the use of anticancer agents. We also summarize the signaling cascades and the specific markers of stomach-cancer-derived organoids induced by H. p. infection, and their stem cell niches.

Cancer during Pregnancy: A Review of Preclinical and Clinical Transplacental Transfer of Anticancer Agents.

Simple SummaryThe use of anti-cancer treatments in pregnant women is an increasingly common situation given the increasing age at first pregnancy. The aim of this study is to review data concerning the transplacental transfer of drugs that can be used in the management of the most common pregnancy-associated cancers. This work is intended to guide clinicians in the choice of the treatments that offer the best benefit–risk ratio for the mother and the fetus and to deliver balanced information to pregnant patients.The occurrence of cancer during pregnancy is observed in 1 in 1000 pregnancies and is expected to increase given the trend of delaying childbearing. While breast cancer is the most common, the incidence of other cancers, such as cervical, ovarian, and lung cancers as well as hemopathies and melanomas, is also increasing. Thus, cancer occurrence in pregnant women raises questions of management during pregnancy and, especially, assessment of the treatment benefit–risk ratio to ensure optimal management for the mother while ensuring the safety of the fetus. Chemotherapy remains a cornerstone of cancer management. If the use of anticancer agents appears possible during pregnancy, while avoiding the first trimester, the extent of placental transfer of different anticancer agents varies considerably thereafter. Furthermore, the significant physiological pharmacokinetic variations observed in pregnant women may have an impact on the placental transfer of anticancer agents. Given the complexity of predicting placental transfer of anticancer agents, preclinical studies are therefore mandatory. The aim of this review was to provide updated data on in vivo and ex vivo transplacental transfer of anticancer agents used in the management of the most common pregnancy-associated cancers to better manage these highly complex cases.

Prevalence and prognosis in cancer therapy-related cardiovascular diseases from big data of electronic health record in Japan

Abstract Background Recent advance in cancer therapy has improved the cancer prognosis, which also increased the number of elder cancer survivors. Yet the anticancer agents have some serious side effects on cardiovascular system. Although there have been previous studies regarding cancer-specific and/or therapeutic agents-specific cardiovascular side effects in the selected patients, real-world data of the epidemiology for the impact of cardiovascular diseases (CVD) in cancer survivors is still limited due to the lack of comprehensive dataset. In this regard, the electronic health record (EHR), a big data, from the National Health Insurance in Japan provides a unique opportunity to obtain the suitable dataset. Purpose The purpose of this study was to clarify the prevalence of various CVD after the use of anticancer agents and the prognosis in cancer survivors using EHR in Japan. Methods This study was a retrospective cohort study using the database of Medical Data Vision (MDV) Co., Ltd. (Tokyo, Japan). The database covered 129 hospitals of all of the Designated Cancer Hospitals in Japan. The total number of patients was 17.85 million, which covered 14% of the total Japanese population. We extracted 140,327 cancer patients who received anticancer agents between April 2008 to January 2017. We identified CVD as pulmonary thromboembolism (PTE), atrial fibrillation (AF), ischemic heart disease (IHD), ventricular arrhythmia, pericarditis patients after the use of anticancer agents, according to International Classification of Diseases, 10th revision (ICD-10) codes. Hypertension (HT) patients were also identified according to ICD-10 codes, with the use of one or more anti-HT drugs after the HT diagnosis. Results The mean follow-up period was 1.53 years and mean age (standard deviation) was 69.2 (11.6) years old. The population over 75 years old were 36.2%, while males were 59.0%. There were prostate cancer (28.3%), lung cancer (13.8%), and colon cancer (13.2%) in males, and breast cancer (43.1%), colon cancer (12.6%), and lung cancer (8.6%) in females. Among them, 3,371 patients (2.4%) were diagnosed as PTE, 2,193 patients (1.6%) as AF, 4,085 patients (2.9%) as stable coronary artery disease, 681 patients (0.5%) as acute myocardial infarction (AMI), 749 patients (0.5%) as ventricular arrhythmia, 238 patients (0.2%) as pericarditis, 7,693 patients (5.5%) as HT. The cumulative survival rate was 65.6% in all cancer patients, 50.7% in PTE, 53.4% in AF, 61.7% in stable coronary disease, 52.7% in AMI and 45.9% in HT after the use of anticancer agents. Conclusion This study indicated that the prevalence of each CVD was less than 10% after the use of anticancer agents, but that patients with cancer therapy-related CVD had worse prognosis. Funding Acknowledgement Type of funding source: None

Asiatic Acid, Extracted from Centella asiatica and Induces Apoptosis Pathway through the Phosphorylation p38 Mitogen-Activated Protein Kinase in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells.

Nasopharyngeal carcinoma (NPC) is an important issue in Asia because of its unique geographical and ethnic distribution. Cisplatin-based regimens are commonly the first-line used chemotherapy, but resistance and toxicities remain a problem. Therefore, the use of anticancer agents derived from natural products may be a solution. Asiatic acid (AA), extracted from Centella asiatica, was found to have anticancer activity in various cancers. The aim of this study is to examine the cytotoxic effect and mediated mechanism of AA in cisplatin-resistant NPC cells. The results shows that AA significantly reduce the cell viability of cisplatin-resistant NPC cell lines (cis NPC-039 and cis NPC-BM) in dose and time dependent manners caused by apoptosis through the both intrinsic and extrinsic apoptotic pathways, including altered mitochondrial membrane potential, activated death receptors, increased Bax expression, and upregulated caspase 3, 8, and 9. The Western blot analysis of AA-treated cell lines reveals that the phosphorylation of MAPK pathway proteins is involved. Further, the results of adding inhibitors of these proteins indicates that the phosphorylation of p38 are the key mediators in AA-induced apoptosis in cisplatin-resistant human NPC cells. This is the first study to demonstrate the AA-induced apoptotic pathway through the phosphorylation p38 in human cisplatin-resistant nasopharyngeal carcinoma. AA is expected to be another therapeutic option for cisplatin-resistant NPC because of the promising anti-cancer effect and fewer toxic properties.

Advantages and Limitations in the Use of Combination Therapies with Charged Particle Radiation Therapy.

Studies are currently underway to help provide basic and clinical evidence for combination particle beam radiation therapy, on which there are few published reports. The purpose of this article is to summarize the current status in the use of particle beams combined with other modalities. Following from experiences in x-ray radiation therapy, combination therapy with proton beams (PBT) has been attempted, and several clinical studies have reported improved survival rates for patients with non-small cell lung cancer, pancreatic cancers, esophageal cancers, and glioblastomas. Recently, basic studies combining PBT with PARP inhibitors and histone deacetylase inhibitors have also reported promising results. In the area of carbon ion therapy (CIT), there are few clinical reports on combination therapy; however, the number of basic research reports exceeds that for PBT. So far, the combined use of cytotoxic drugs with CIT yields independent additive effects. In addition, it is notable that combination therapy with CIT is effective against radioresistant cancer stem-like cells. Recent evidence also suggests that local radiation therapy can induce an effective antitumor immune response. There has been an increased use of combination immune-modulating agents and cytokines with particle beams, especially CIT. The field of radiation therapy is evolving from a strong reliance on local-regional treatment to a growing reliance on systemic immunotherapy. The combined use of anticancer agents with particle radiation therapy has a considerable potential effect. Future research in molecular targeting therapy and immunotherapy may help identify the most efficacious approach for combination therapy with protons and carbon ions.

MP54-02 DEVELOPMENT OF INTRAVESICAL HUMAN γΔT CELL BASED CHEMO-IMMUNOTHERAPY AGAINST URINARY BLADDER CANCER CELLS IN AN ORTHOTOPIC XENOGRAFT MODEL

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I1 Apr 2018MP54-02 DEVELOPMENT OF INTRAVESICAL HUMAN γΔT CELL BASED CHEMO-IMMUNOTHERAPY AGAINST URINARY BLADDER CANCER CELLS IN AN ORTHOTOPIC XENOGRAFT MODEL Teruki Shimizu, Mako Tomogane, Masatsugu Miyashita, Osamu Ukimura, and Eishi Ashihara Teruki ShimizuTeruki Shimizu More articles by this author , Mako TomoganeMako Tomogane More articles by this author , Masatsugu MiyashitaMasatsugu Miyashita More articles by this author , Osamu UkimuraOsamu Ukimura More articles by this author , and Eishi AshiharaEishi Ashihara More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1693AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Intravesical BCG treatment continues to play a central role in the treatment of non-muscle invasive urinary bladder cancer (UBC). There is currently no gold standard for salvage intravesical therapy after BCG treatment failure. To develop the substitute for BCG treatment failure, we focused on γδT cell immunotherapy. γδT cells exert potent cytotoxicity towards various cancer cells and can recognize isopentenyl pyrophosphate (IPP) through the TCRγδ receptor, and zoredronic acid (ZOL) pretreatment is widely used to induce IPP accumulation in cancer cells. In this study, we hilighted two issues; combined use of anticancer agents along with ZOL and a bladder instillation approach. The aims are to improve recognition of cancer cells by γδT cells and to increase E/T (Effector/Target) ratio. METHODS We examined the efficacy of ex vivo-expanded γδT cell immunotherapy. Flow cytometric analysis of CFSE/propidium iodide (PI) staining was used in in vitro cytotoxicity assays.After co-culture for 4 h, CFSE/PI double positive population was measured as apoptotic cancer cells. In in vivo experiment, the efficacy of ex vivo-expanded γδT cell immunotherapy was examined in an orthotopic xenograft model using In Vivo Imaging System (IVIS). RESULTS Ex vivo-expanded γδT cells showed potent cytotoxicity against UBC cells in in vitro assays. Combination treatment with standard anticancer agents showed that low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of γδT cells by upregulating the expression of MICA and MICB (MICA/B), which are tumor-associated antigens recognized by γδT cells. These effects were abrogated by small interfering RNA-mediated knockdown of MICA/B in UBC cells. IVIS analysis revealed the potent cytotoxicity of weekly intravesical administration of γδT cells (Figure. 1), and weekly gemcitabine pretreatment enhanced the cytotoxicity of γδT cells in vivo. CONCLUSIONS Low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of γδT cells by upregulating the expression MICA/B in in vitro. Intravesical γδT cell immunotherapy exerted potent cytotoxicity against UBC and intravesical γδT cell immunotherapy in combination with low dose gemcitabine may be a promising strategy in UBC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e712 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Teruki Shimizu More articles by this author Mako Tomogane More articles by this author Masatsugu Miyashita More articles by this author Osamu Ukimura More articles by this author Eishi Ashihara More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Identifying the Best Anticancer Agent Combination in TACE for HCC Patients: A Network Meta-analysis.

Objective: We conducted a network meta-analysis to comprehensively compare various anticancer agents used in transarterial chemoembolization (TACE) based on the Bayesian theorem.Methods: Globally recognized electronic databases, including PubMed, EMBASE, and Cochrane Central, were searched to retrieve relevant randomized controlled trials (RCTs) comparing anticancer agents in TACE for hepatocellular carcinoma (HCC) patients. The therapeutic response, adverse events and overall survival rate were selected as parametric data to evaluate the clinical efficacy. Quantitative network meta-analysis and pair-wise analysis were conducted to compare the relative parameters.Results: Of the 4242 retrieved articles, 17 RCTs containing 2330 patients fulfilled the inclusion criteria. The network meta-analysis exhibited that the application of anthracycline and mitomycin plus pyrimidine presented the best clinical values regarding all parametric data (probability P=0.45, 0.32 and 0.35 regarding comparison of response rate, adverse event and overall survival, respectively). Accordingly, further investigation on specific anticancer agents indicated that the combination of doxorubicin and mitomycin plus gemcitabine was the best agent combination in TACE (probability P=0.49, 0.37 and 0.77 regarding comparison of response rate, adverse event and overall survival, respectively). Moreover, an additional study indicated that the single use of an anticancer agent prior to embolism brought no benefit compared with bland embolism without any agent (Test Z=0.15, 0.84, 1.22 and P=0.88, 0.40, 0.22 regarding comparison of response rate, adverse event and overall survival, respectively). However, the combined use of anticancer agents in TACE showed significantly better clinical efficacy than single use (Test Z=4.40, 3.94, 0.24 and P<0.001, <0.001, =0.81 regarding comparison of response rate, adverse event and overall survival, respectively); thus, combination utilization was recommended.Conclusions: The combined use of anticancer agents in TACE was recommended. Application of anthracycline and mitomycin plus pyrimidine seemed to be the best choice for clinical consideration. Additionally, the combination of doxorubicin and mitomycin plus gemcitabine may be the best specific anticancer agent combination in TACE currently, although additional RCTs are expected to support our conclusion.

Localized delivery of therapeutic doxorubicin dose across the canine blood–brain barrier with hyperthermia and temperature sensitive liposomes

Most drugs cannot penetrate the blood–brain barrier (BBB), greatly limiting the use of anti-cancer agents for brain cancer therapy. Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug in response to hyperthermia (>40 °C). Since hyperthermia also transiently opens the BBB, we hypothesized that localized hyperthermia can achieve drug delivery across the BBB when combined with TSL. TSL-encapsulated doxorubicin (TSL-Dox) was infused intravenously over 30 min at a dose of 0.94 mg/kg in anesthetized beagles (age ∼17 months). Following, a hyperthermia probe was placed 5–10 mm deep through one of four 3-mm skull burr holes. Hyperthermia was performed randomized for 15 or 30 min, at either 45 or 50 °C. Blood was drawn every 30 min to measure TSL-Dox pharmacokinetics. Nonsurvival studies were performed in four dogs, where brain tissue at the hyperthermia location was extracted following treatment to quantify doxorubicin uptake via high-performance liquid chromatography (HPLC) and to visualize cellular uptake via fluorescence microscopy. Survival studies for 6 weeks were performed in five dogs treated by a single hyperthermia application. Local doxorubicin delivery correlated with hyperthermia duration and ranged from 0.11 to 0.74 μg/g of brain tissue at the hyperthermia locations, with undetectable drug uptake in unheated tissue. Fluorescence microscopy demonstrated doxorubicin delivery across the BBB. Histopathology in Haematoxylin & Eosin (H&E) stained samples demonstrated localized damage near the probe. No animals in the survival group demonstrated significant neurological deficits. This study demonstrates that localized doxorubicin delivery to the brain can be facilitated by TSL-Dox with localized hyperthermia with no significant neurological deficits.

2nd Symposium on Advances in Cancer Immunology and Immunotherapy, December 15-17, 2016, Athens, Greece.

This is the 2nd Symposium of a series organized annually. It aims to integrate tumor immunology basic research with results from most recent clinical trials based on the use of anti-cancer agents targeting immune system components.

Application of a shared interdisciplinary and multiprofessional cardio-oncology in-hospital pathway

The burden of cardiac side effects in oncology patients will dramatically increase in the near future as a result of the widespread use of anticancer agents affecting the cardiovascular system, the general population aging, the heightened attention in the detection of cardiac toxicity and the absolute gain in terms of overall survival. The relationship between cardiologists and oncologists should therefore be closer leading to the definition of cardio-oncology. The increased number of such patients requires the creation of a dedicated patient assistance program in order to guarantee every patient the possibility of an interdisciplinary and multiprofessional approach. A dedicated care pathway needs a reorganization of internal resources to ensure high standards of care. The proposed pathway is actually active at our institution and has been implemented taking into account available facilities and planned work amount. Our patient cardio-oncology program could be adapted with minimal changes to different hospitals.

Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity?

Signalling pathways involving protein kinase, insulin-like growth factor 1, insulin receptors and the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) system are critical in promoting oncogenesis. The use of anticancer agents that inhibit these pathways frequently results in hyperglycaemia, an on-target effect of these drugs. Hyperglycaemia induced by these agents denotes optimal inhibition of the desired pharmacological target. As hyperglycaemia can be treated successfully and effectively with metformin, managing this complication by reducing the dose of or discontinuing the anticancer drug may be counterproductive, especially if it is otherwise effective and clinically tolerated. The use of metformin to treat hyperglycaemia induced by anticancer drugs provides a valuable therapeutic opportunity of potentiating their clinical anticancer effects. Although evidence from randomised controlled trials is awaited, extensive preclinical evidence and clinical observational studies suggest that metformin has anticancer properties that improve overall survival in patients with diabetes and a variety of cancers. Metformin has also been reported to reverse resistance to epidermal growth factor receptor (EGFR)-inhibiting tyrosine kinase inhibitors. This review summarises briefly the role of the above signalling pathways in oncogenesis, the causal association between inhibition of these pathways and hyperglycaemia, and the effect of metformin on clinical outcomes resulting from its anticancer properties. The evidence reviewed herein, albeit almost exclusively from observational studies, provides support for a greater use of metformin not only in patients with cancer and diabetes or drug-induced hyperglycaemia but also potentially as an anticancer drug. However, prospective randomised controlled studies are needed in all these settings to better assess the effect on clinical outcomes of adding metformin to ongoing anticancer therapy.

Treatment of Liver Tumors with Lipiodol TACE: Technical Recommendations from Experts Opinion.

Transarterial chemoembolization with Lipiodol (Lipiodol TACE), also called conventional TACE, was developed in the early 1980s and widely adopted worldwide after randomized control trials and meta-analysis demonstrated superiority of Lipiodol TACE to best supportive care. Presently, there is no level one evidence that other TACE techniques are superior to Lipiodol TACE for intermediate stage hepatocellular carcinoma (HCC), which includes patients with preserved liver function and nonsurgical large or multinodular HCC without distant metastases. In addition, TACE is part of the treatment for progressive or symptomatic liver metastases from gastroenteropancreatic neuroendocrine tumors. When injected into the hepatic artery, Lipiodol has the unique property of selective uptake and retention in hyperarterialyzed liver tumors. Lipiodol/drug emulsion followed by particle embolization has been demonstrated to improve the pharmacokinetic of the drug and tumor response. Radio opacity of Lipiodol helps to monitor treatment delivery, with retention of Lipiodol serving as an imaging biomarker for tumor response. For 30 years, Lipiodol TACE has been inconsistently referenced in many publications with various levels of details for the method of preparation and administration, with reported progressive outcomes following improvements in the technique and the devices used to deliver the treatment and better patient selection. Consequently, there is no consensus on the standard method of TACE regarding the use of anticancer agents, embolic material, technical details, and the treatment schedule. In order to develop an internationally validated technical recommendation to standardize the Lipiodol TACE procedure, a worldwide panel of experts participated in a consensus meeting held on May 10, 2014 .

Deoxyribonucleotide metabolism, mutagenesis and cancer.

Cancer was recognized as a genetic disease at least four decades ago, with the realization that the spontaneous mutation rate must increase early in tumorigenesis to account for the many mutations in tumour cells compared with their progenitor pre-malignant cells. Abnormalities in the deoxyribonucleotide pool have long been recognized as determinants of DNA replication fidelity, and hence may contribute to mutagenic processes that are involved in carcinogenesis. In addition, many anticancer agents antagonize deoxyribonucleotide metabolism. Here, we consider the extent to which aspects of deoxyribonucleotide metabolism contribute to our understanding of both carcinogenesis and to the effective use of anticancer agents.

Abstract 5500: A 3D tumor tissue microphysiological system for realistic tumor microenvironment mimicry and therapeutic modeling

Abstract Introduction: Although cancer is a heterogeneous disease, current chemotherapy is based on the use of anti-cancer agents that broadly affect cell proliferation. As a result of this non-specific tumor therapy there is often high toxicity and therapeutic resistance, which increases the risk of disease progression. There is thus a critical need to find novel anti-cancer compounds, however, as a result of preliminary screens often performed in 2D systems, and the use of mouse models for secondary screens, many drugs fail during full clinical trials. Replicating a complex, 3D microenvironment incorporating human cells is therefore likely to improve drug screening efficiency. Methods: Here we have developed a system for high throughput screening of drug efficacy. Our system features 3D tumor tissues incorporating human cells co-cultured with stromal cells and connected by human microvessels in a naturally occurring 3D matrix in a PDMS microdevice. Transduced colorectal cancer cells (CRC) such as HCT116, SW480 and SW620s that express green fluorescent protein (GFP) constitutively are introduced into the device in co-culture with human endothelial colony-forming cell-derived EC (ECFC-EC) and fibroblasts. ECFC-EC or fibroblasts that express longer wavelength fluorescent proteins are also used to track both tumor cells and vasculature/fibroblast growth. The tri-culture is resuspended in fibrinogen (10 mg/ml) and mixed with thrombin before injecting into the microchambers. Cells are fed with endothelial growth media-2 and drugs are delivered through the microfluidic channels using a hydrostatic pressure gradient. Results: A complete vascular network was formed in the chambers by 7-10 days and this carried medium into the tissue. CRC showed continuous growth, often forming spheroids. After 7-10 days of culture, cells were exposed to various FDA-approved drugs at concentrations reported for plasma levels in patients. Tumor growing in the device responded differently to most drugs compared to cells growing in 2D. We identified cytotoxic and cytostatic drug actions in the device with IC50s close to the in vivo pharmacologic plasma concentration, but higher than those obtained in parallel 2D experiments. Importantly, we also identified drugs that were active in our 3D-device but not in 2D cultures. Conclusions: Preliminary results using our 3D microphysiological system, in which we have created a more complex microenvironment than used in 2D cultures, support an improved strategy for drug validation. In addition, future experiments will include the use of non-invasive optical imaging techniques to better understand the human 3D tumor microenvironment, including the study of different tumor behaviors, tumor metabolism and pathological angiogenesis. This proof-of-concept study validates the use of 3D microphysiological systems in place of more simplistic 2D systems. Citation Format: Agua Sobrino, Dúc Phan, Steven C George, Christopher C.W Hughes. A 3D tumor tissue microphysiological system for realistic tumor microenvironment mimicry and therapeutic modeling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5500. doi:10.1158/1538-7445.AM2015-5500

Protective effect of quercetin on melphalan-induced oxidative stress and impaired renal and hepatic functions in rat.

One major challenge with the use of anticancer agents is the phenomenon of drug-induced toxicity. Melphalan (MPLN) is an alkylating anticancer agent, while quercetin (QCT) is an antioxidant. We investigated the protective role of quercetin against MPLN-induced toxicity. Twenty-five male Wistar rats (160–170 g) were randomized into five treatment groups; (I) control, (II) MPLN (0.2 mg/kg b.w.), (III) pre-treated with QCT (20 mg/kg b.w.) for 7 days followed by MPLN (0.2 mg/kg b.w.) for 7 days, (IV) cotreated with QCT (20 mg/kg b.w.) and MPLN (0.2 mg/kg b.w.) for 7 days, and (V) QCT (20 mg/kg b.w.) alone. MPLN caused a significant increase in plasma bilirubin, urea, and creatinine by 122.2%, 102.3%, and 188%, respectively (P < 0.05). Similarly, plasma ALP, ALT, AST, and γ-GT activities increased significantly by 57.9%, 144.3%, 71.3%, and 307.2%, respectively, relative to control. However, pre or cotreatment with QCT ameliorated the levels of renal and hepatic function indices. Hepatic ascorbic acid and GSH and activities of glutathione-S-transferase, SOD, and catalase decreased significantly by 36.2%, 188%, 46.5%, 34.4%, and 55.2%, respectively, followed by increase in MDA content by 46.5% relative to control. Pre- and cotreatment with QCT reestablished the hepatic antioxidant status and lipid peroxidation. Overall, quercetin protected against MPLN-induced renal and hepatic toxicity in rats.