Review article: new therapeutic interventions for advanced hepatocellular carcinoma.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) portends a poor prognosis; however recent advances in first-line and second-line treatment options should yield significant improvements in survival. AIM: To summarize the evolving landscape of treatment options for patients with advanced HCC. METHODS: We reviewed published clinical trials conducted in patients with advanced HCC published in PubMed or presented at national conferences. RESULTS: Sorafenib was approved for treatment of unresectable HCC in 2007 and remained the only therapy with proven survival benefit in advanced HCC for several years. Lenvatinib, another tyrosine-kinase inhibitor, was recently shown to have non-inferior survival vs sorafenib and is another first-line treatment option. The tyrosine-kinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second-line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second-line setting among patients with AFP ≥ 400 ng/dL. Phase II data highlight potential durable objective responses with immune checkpoint inhibitors, prompting conditional FDA approval of nivolumab and pembrolizumab in the second-line setting; however, recent phase III data have failed to demonstrate improved survival compared to other treatment options. Ongoing trials are evaluating combination immune checkpoint inhibitor and immune checkpoint inhibitors with tyrosine-kinase inhibitors or VEGF inhibitors in hopes of further increasing objective responses and overall survival in this patient population. CONCLUSION: There are several first-line and second-line therapeutic options available for patients with advanced HCC. Further studies are needed to determine how best to select between and sequence the growing number of therapeutic options.

Curcumina, una alternativa térapéutica para la clínica dental. Parte: antiinflamatorio y analgésico / Curcumin, a therapeutic alternative for the dental clinic (Part I):An anti-inflammatory and analgesic

La curcumina es una sustancia derivada de una planta llamada Curcuma longa. A esta sustancia se le han atribuido diversos efectos terapéuticos. En relación con la clínica dental, se ha observado que, además de ayudaren el control del dolor, ha sido efectiva contra la periodontitis, estomatitis y mucositis pediátrica. El control del dolor e inflamación son aspectos muy importantes para la mayoría de los tratamientos en odontología; la búsqueda de nuevas alternativas analgésicas y antiinflamatorias que, en comparación con las actuales, sean más eficientes, efectivas y tengan menos efectos colaterales es uno de los grandes retos de las ciencias biomédicas. La presente revisión muestra algunas evidencias científicas de los efectos de la curcumina como un antiinflamatorio y analgésico, con el propósito de sentar las bases para futuros estudios clínicos y de ciencia básica que aporten un mayor entendimiento de los procesos celulares, bioquímicos, moleculares, fisiológicos y farmacológicos de la curcumina como una sustancia potencialmente útilen el consultorio dental.

Curcumin is a substance derived from the plant Curcuma longa andone that has been attributed a range of therapeutic eff ects. In dentalpractice, curcumin has not only been found to help with pain control, buthas also been eff ective against periodontitis, stomatitis, and pediatricmucositis. Controlling pain and infl ammation are both very importantaspects of most dental treatments. The search for more effi cient andeff ective analgesic and anti-infl ammatory alternatives with fewerside eff ects compared to those currently used is one of the greatestchallenges for biomedical science. This review presents some of thescientifi c evidence of the eff ects of curcumin, both as an analgesic andan anti-infl ammatory agent, in order to establish the foundations forfurther clinical and basic science studies that will provide a greaterunderstanding of the cellular, biochemical, molecular, physiological,and pharmacological processes of curcumin as a potentially usefulsubstance in dental practice.

[Pharmacogenomics of the first-line treatment for gastric cancer: advances in the identification of genomic biomarkers for clinical response to chemotherapy]. / Farmacogenómica del tratamiento de primera linea en el cáncer gástrico: avances en la identificación de los biomarcadores genómicos de respuesta clínica.

Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.

Farmacogenómica del tratamiento de primera línea en el cáncer gástrico: avances en la identificación de los biomarcadores genómicos de respuesta clínica / Pharmacogenomics of the first-line treatment for gastric cancer: advances in the identification of genomic biomarkers for clinical response to chemotherapy

Debido a la inespecificidad de los síntomas, el cáncer gástrico (CG) es diagnosticado frecuentemente en etapas avanzadas, lo que da cuenta de los altos índices de mortalidad debido a esta neoplasia a nivel mundial. El esquema de tratamiento adyuvante o neoadyuvante en los países occidentales incluye el uso de fluoropirimidinas citotóxicas y compuestos de platino formadores de aductos en el ADN. La respuesta clínica al tratamiento con estos fármacos depende principalmente de la sensibilidad del tumor, la cual a su vez está condicionada por el nivel de expresión de los blancos terapéuticos y de las enzimas de reparación del ADN. Sumado a esto, algunos polimorfismos de línea germinal en genes asociados al metabolismo y a la respuesta a estos fármacos, han mostrado asociación con respuestas pobres y con el desarrollo de eventos adversos, incluso con resultados fatales. La identificación de biomarcadores genómicos, en la forma de polimorfismos genéticos o la expresión diferencial de genes específicos asociados a la respuesta quimioterapeútica ha sido motivo de intensa investigación como base para la aplicación de la farmacogenómica en el establecimiento de una terapia farmacológica racional y personalizada del CG. Sin embargo, ante la eventual aplicación de la farmacogenómica en el ámbito clínico, es necesario establecer el valor pronóstico real de dichos biomarcadores mediante los estudios de asociación genotipo-fenotipo, así como su prevalencia en el contexto de cada población de pacientes. Estos aspectos son indispensables al evaluar la relación costo-efectividad de la introducción de los productos de la medicina genómica predictiva en el tratamiento del CG.

Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.

BRAF inhibitors: From the laboratory to clinical trials.

BRAF is one of the most commonly mutated proto-oncogenes and plays a significant role in the development of numerous cancers of high clinical impact. Due to the commonality of BRAF mutations, a number of BRAF inhibitors have been developed as tools in the management of patients with cancers dependent on the action of mutant BRAF to drive cellular proliferation. In this review, we examine the current state of clinical trials and laboratory research concerning BRAF inhibitors in development and available for clinical use. We contrast the effectiveness of type-I and type-II BRAF inhibitors, the former typically showing much more restricted inhibitory selectivity and greater patient response rates.

Drug interactions with solid tumour-targeted therapies.

Drug interactions are an on-going concern in the treatment of cancer, especially when targeted therapies, such as tyrosine kinase inhibitors (TKI) or mammalian target of rapamycin (mTOR) inhibitors, are being used. The emergence of elderly patients and/or patients with both cancer and other chronic co-morbidities leads to polypharmacy. Therefore, the risk of drug-drug interactions (DDI) becomes a clinically relevant issue, all the more so as TKIs and mTOR inhibitors are essentially metabolised by cytochrome P450 enzymes. These DDIs can result in variability in anticancer drug exposure, thus favouring the selection of resistant cellular clones or the occurrence of toxicity. This review provides a comprehensive overview of DDIs that involve targeted therapies approved by the FDA for the treatment of solid tumours for more than 3 years (sorafenib, sunitinib, erlotinib, gefitinib, imatinib, lapatinib, everolimus, temsirolimus) and medicinal herb or drugs. This review also provides some guidelines to help oncologists and pharmacists in their clinical practice.

TIPdb: a database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan.

The unique geographic features of Taiwan are attributed to the rich indigenous and endemic plant species in Taiwan. These plants serve as resourceful bank for biologically active phytochemicals. Given that these plant-derived chemicals are prototypes of potential drugs for diseases, databases connecting the chemical structures and pharmacological activities may facilitate drug development. To enhance the utility of the data, it is desirable to develop a database of chemical compounds and corresponding activities from indigenous plants in Taiwan. A database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan was constructed. The database, TIPdb, is composed of a standardized format of published anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan. A browse function was implemented for users to browse the database in a taxonomy-based manner. Search functions can be utilized to filter records of interest by botanical name, part, chemical class, or compound name. The structured and searchable database TIPdb was constructed to serve as a comprehensive and standardized resource for anticancer, antiplatelet, and antituberculosis compounds search. The manually curated chemical structures and activities provide a great opportunity to develop quantitative structure-activity relationship models for the high-throughput screening of potential anticancer, antiplatelet, and antituberculosis drugs.

Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors.

Inhibiting angiogenesis has become an important therapeutic strategy for cancer treatment but, like other current targeted therapies, benefits experienced for late-stage cancers can be curtailed by inherent refractoriness or by acquired drug resistance, requiring a need for better mechanistic understanding of such effects. Numerous preclinical studies have demonstrated that VEGF pathway inhibitors suppress primary tumour growth and metastasis. However, it has been recently reported that short-term VEGF and VEGFR inhibition can paradoxically accelerate tumour invasiveness and metastasis in certain models. Here we comprehensively compare the effects of both antibody and small molecule receptor tyrosine kinase (RTK) inhibitors targeting the VEGF-VEGFR pathway, using short-term therapy in various mouse models of metastasis. Our findings demonstrate that antibody inhibition of VEGF pathway molecules does not promote metastasis, in contrast to selected small molecule RTK inhibitors at elevated-therapeutic drug dosages. In particular, a multi-targeted RTK inhibitor, sunitinib, which most profoundly potentiated metastasis, also increased lung vascular permeability and promoted tumour cell extravasation. Mechanistically, sunitinib, but not anti-VEGF treatment, attenuated endothelial barrier function in culture and caused a global inhibition of protein tyrosine phosphorylation, including molecules important for maintaining endothelial cell-cell junctions. Together these findings indicate that, rather than a specific consequence of inhibiting the VEGF signalling pathway, pharmacological inhibitors of the VEGF pathway can have dose- and drug class-dependent side-effects on the host vasculature. These findings also advocate for the continued identification of mechanisms of resistance to anti-angiogenics and for therapy development to overcome it.

Cardiotoxicity of molecularly targeted agents.

Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. In this review, we summarize the classification and side effects of currently approved molecularly targeted chemotherapeutics.

Preclinical development of molecular-targeted agents for cancer.

Molecular-targeted agents are increasingly used for the treatment of cancer. However, the attrition rate for drugs that enter early clinical trials is higher than for other branches of internal medicine, suggesting that preclinical development has not been successful in identifying agents that can modify the outcome of human cancer. New preclinical strategies including genetically engineered mouse models and small-interfering RNAs are being used to evaluate novel agents, and have aided in the development of compounds, such as inhibitors of phosphatidylinositol 3-kinase or poly(ADP-ribose) polymerase. In addition, these techniques have helped in the identification of promising combinations of targeted drugs. In this Review, we describe methods for the preclinical evaluation of novel agents, their limitations, and strategies for improvement.

An onco-informatics database for anticancer drug interactions with complementary and alternative medicines used in cancer treatment and supportive care: an overview of the OncoRx project.

PURPOSE: Cancer patients are at high risk of manifesting interactions from use of anticancer drugs (ACDs) and complementary and alternative medicines (CAMs). These interactions can result in sub-therapeutic effects or increased toxicities which may compromise the outcome of chemotherapy. It is important for practitioners to gain convenient access to ACD-CAM interaction information so as to make better-informed decisions in daily practice. This paper describes the creation of an oncology database (OncoRx) that documents ACD-CAM interactions, including traditional Chinese medicines (TCMs) that are commonly used for cancer treatment, prevention, and supportive care therapy. METHODS: Information regarding ACDs, CAMs, and drug interactions were collated from 14 sources, inclusive of hardcopy and online resources, and input into a modified web server with a database engine and a programming interface using a combination of software and programming scripts. RESULTS: OncoRx currently contains a total of 117 ACDs and 166 CAMs. Users are able to search for interactions based on various CAM uses: cancer treatment or prevention, immune-system-related, alopecia, nausea, and vomiting, peripheral neuropathy and pain, inflammation, fatigue, and non-cancer related. Pharmacokinetic data on ACDs and CAMs, characteristics of CAMs based on TCM principles, and drug interaction parameters such as effects, mechanisms, evidences, and proposed management plans, are shown in the search results. CONCLUSION: OncoRx is an oncology database which detects ACD interactions. It is currently able to detect interactions with CAMs. It is hoped that OncoRx will serve as a useful resource to clinicians, educators, trainers, and students working in the oncology setting.

[Using a new generation of classification system of antineoplastic drugs to guide Chinese medicine research].

A new generation of classification system of antineoplastic drugs was put forward based on comparing the first with the second generation classification system of antineoplastic drugs. Antineoplastic drugs are divided into cytotoxic drug, cells biological behavior regulator, biological response modifier and biochemical modulator. The using of biological response modifier (immune modulator for instance) and biochemical modulator are supplementary methods for Western medicine treatment in tumor, because the cytotoxic effects of Chinese herbs are lower than those of chemotherapeutic drugs. For the new breakthrough of Chinese medicine oncology research, new idea, new technology and new target should be used, the Chinese medicine mechanism should be studied from a new view. Reversing abnormal biological behavior of tumor cells by Chinese medicine could be an important breakthrough of Chinese medicine oncology research.

An examination of chimpanzee use in human cancer research.

Advocates of chimpanzee research claim the genetic similarity of humans and chimpanzees make them an indispensable research tool to combat human diseases. Given that cancer is a leading cause of human death worldwide, one might expect that if chimpanzees were needed for, or were productive in, cancer research, then they would have been widely used. This comprehensive literature analysis reveals that chimpanzees have scarcely been used in any form of cancer research, and that chimpanzee tumours are extremely rare and biologically different from human cancers. Often, chimpanzee citations described peripheral use of chimpanzee cells and genetic material in predominantly human genomic studies. Papers describing potential new cancer therapies noted significant concerns regarding the chimpanzee model. Other studies described interventions that have not been pursued clinically. Finally, available evidence indicates that chimpanzees are not essential in the development of therapeutic monoclonal antibodies. It would therefore be unscientific to claim that chimpanzees are vital to cancer research. On the contrary, it is reasonable to conclude that cancer research would not suffer, if the use of chimpanzees for this purpose were prohibited in the US. Genetic differences between humans and chimpanzees, make them an unsuitable model for cancer, as well as other human diseases.

The prince and the pauper. A tale of anticancer targeted agents.

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.

Terapias de soporte / Supportive therapy

Uno de los factores que han contribuido de manera decisiva a la mejora de los resultados terapéuticos en los niños con cáncer, ha sido la utilización sistemática de una serie de medidas que han permitido disminuir los efectos tóxicos derivados de la propia terapia. La terapia de soporte engloba todas aquellas medidas dirigidas a la prevención y tratamiento de las complicaciones derivadas de la propia enfermedad o del tratamiento de la misma (AU)

One of the factors that has decisively contributed to the improvement of therapeutic results in children with cancer has been the systematic use of a series of measures that has made it possible to decrease the toxic effects derived form the therapy itself. Supportive therapy includes all those measures aimed at prevention and treatment of the complications cause by the disease itself or from its treatment (AU)

Antitumor activity of extracts and compounds from the rhizomes of Veratrum dahuricum.

The antitumor activity of six extracts (ethanol extract, petroleum ether fraction, CHCl(3) fraction, ethyl acetate fraction, n-butanol fraction and total alkaloids) from the rhizomes of Veratrum dahuricum, and six compounds (veratramine (1), jervine (2), germine (3), veramitaline (4), veratrosine (5) and cyclopamine (6)) from the ethanol extract were investigated in vitro. The 12 samples exhibited cytotoxic activity against human tumor cell lines A549, PANC-1, SW1990 and NCI-H249. Among these samples, CHCl(3) fraction, the total alkaloids, compounds 1 and 6 showed higher inhibitory activity, compound 3 selectively exhibited significant cytotoxicity to SW1990 and NCI-H249.

Comprehensive review of cancer chemopreventive agents evaluated in experimental carcinogenesis models and clinical trials.

Cancer chemoprevention refers to the use of pharmacological agents to inhibit, delay or reverse the multi-step process of carcinogenesis. The last two decades in particular have witnessed explosive growth in this emerging field of cancer chemoprevention. Extensive efforts to evaluate possible application of various chemopreventive agents, in individuals at high risk of neoplastic development have been carried out. Epidemiological studies suggest a protective role of several agents in reducing the risk of cancer. The protective action of all these agents is explained as a combination of various proposed mechanisms involving anti-oxidant, anti-inflammatory, immunomodulatory action, apoptosis induction, molecular association with carcinogen, cell cycle arrest, cell differentiation induction, antimicrobial effect, and anti- angiogenesis etc. Large numbers of candidate substances such as phytochemicals and their synthetic derivatives have been identified by a combination of in vitro and in vivo studies in a wide range of biological assays. However, a comprehensive description of these chemopreventive agents has not been extensively reviewed. In this review we discuss cancer chemopreventive agents in relation to their source, efficacy in cancer chemopreventive action in vivo and epidemiological data. The experimental carcinogenesis studies in different biological models, in addition to the contribution from our laboratory are summarized.