Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples

Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Cancer cells in hypoxic areas of solid tumors are to a large extent protected against the action of radiation as well as many chemotherapeutic drugs. There are, however, two different aspects of the problem caused by tumor hypoxia when cancer therapy is concerned: One is due to the chemical reactions that molecular oxygen enters intoin therapeutically targeted cells. This results in a direct chemical protection against therapy by the hypoxic microenvironment which has little to do with cellular biological regulatory processes. This part of the protective effect of hypoxia has been known for more than half a century and has been studied extensively. However, in recent years more focus has been put into the other aspect of hypoxia, namely the effect of this microenvironmental condition on selecting cells with certain genetical pre-requisites that are negative with respect to patient prognosis. There are adaptive mechanisms, where hypoxia induces regulatory cascades in cells resulting in a changed metabolism or changes in extra cellular signalling. These processes may lead to changes in cellular intrinsic sensitivity to treatment irrespective of oxygenation and furthermore, may also have consequences for tissue organization. Thus, the adaptive mechanisms induced by hypoxia itself may have a selective effect on cells with a fine-tuned protection against damage and stress of many kinds. It therefore could be that the adaptive mechanisms may be taken advantage of for new tumor labelling/imaging and treatment strategies. One of the Achilles’ heels of hypoxia research has always been exact measurements of tissue oxygenation as well as control of oxygenation in biological tumor models. Thus, development of technology that can ease this control is vital in order to study mechanisms and perform drug development under relevant conditions. An integrated EU Framework project 2004-2009, termed Euroxy, demonstrates several pathways involved in transcription and translation control of the hypoxic cell phenotype and evidence of cross talk with responses to pH and redox changes. The carbon anhydrase isoenzyme CA IX was selected for further studies due to its expression on the surface of many types of hypoxic tumors. The effort has lead to marketable culture flaks with sensors and incubation equipment and the synthesis of new drug candidates against new molecular targets. New labelling/imaging methods for cancer diagnosing and imaging of hypoxic cancer tissue now are being tested in xeno-graft models and also are in early clinical testing while new potential anticancer drugs are undergoing tests using xenografted tumor cancers. The present paper describes the above results in individual consortium partner presentations

Gestão econômica de investimentos em ativos fixos

Num ambiente global de intensas mudanças competitivas, a mensuração dos ativos, especificamente dos ativos fixos, requer a superação da rigidez dos custos históricos e da depreciação linear, próprios da contabilidade tradicional, e a adoção de critérios que permitam avaliar adequadamente a realidade econômica desses ativos. Partindo da premissa de que o patrimônio líquido deve representar o valor da empresa, e de que sua variação expressa o resultado econômico, o Sistema de Gestão Econômica - Gecon conceitua e mensura os ativos fixos pelo valor presente dos seus benefícios futuros para a empresa. Como sistema de gestão voltado para decisões econômicas, o Gecon explicita um modelo de decisão para o evento investimento em ativos fixos. Nessa decisão são considerados os custos diretos dela decorrentes, bem como os benefícios econômicos resultantes do uso do ativo fixo pela empresa, mensurados pelo seu custo de oportunidade. Considerando a empresa como conjunto de áreas de responsabilidade conceituadas como centros de resultado, o Gecon identifica a contribuição de cada área envolvida na decisão para a obtenção do resultado econômico do investimento e, portanto, para o resultado da empresa. O fluxo de resultados do investimento é gerenciado durante toda a sua vida útil, desde o momento da tomada de decisão inicial até o momento final da decisão de desativação ou desinvestimento.<br>In a global environment that is going through intense competitive changes, the measurement of assets, specifically fixed assets, makes it necessary to overcome the rigidity of historical costs and straightline depreciation, characteristic of traditional accounting, and to adopt criteria that allow for the adequate evaluation of the economic reality of these assets. Starting from the premise that net equity must represent company value and that its variation expresses economic income, the Economic Management System - Gecon - conceptualizes and measures fixed assets by the present value of their future benefits for the company. As a management system directed towards economic decisions, Gecon formulates a decision model for the investment event in fixed assets. In this decision, the resulting direct costs are considered, as well as the economic benefits that result from the use of the fixed asset by the company, which are measured at their opportunity cost. Considering the company as a set of responsibility areas that are conceived as result centers, Gecon identifies the contribution of each area involved in the decision to the economic income of the investment and, consequently, to company income.The income flow of the investment is managed throughout its useful life, from the initial decision-making moment until the final moment of the deactivation or divestment decision

Internet: desafio para uma contabilidade interativa

O fenômeno explosivo da Internet, insuspeitado há 10 anos, e que hoje se expande de modo acelerado e abrangente em todas as atividades humanas, tem impactos relevantes também na contabilidade. A interatividade, como característica da nova forma de comunicação inaugurada com a Internet, apresenta desafios ao Sistema Contábil Gerencial, cujas respostas, na forma de uma visão interativa da empresa, do patrimônio e do processo de gestão, se expressam na abordagem do Sistema de Gestão Econômica. As insuficiências da Contabilidade Financeira em expressar a realidade das empresas da nova economia no mercado de capitais são igualmente identificadas. Ao mesmo tempo, são comentadas as oportunidades que se abrem à contabilidade financeira, com a divulgação das demonstrações mediante os recursos de linguagem da Internet, com base nos projetos desenvolvidos por entidades reguladoras, particularmente pelo International Accounting Standards Committee (IASC). Com o incremento da comunicação contábil interativa via Internet e com o aprofundamento do debate sobre a contabilização das empresas de ativos intelectuais intensivos, como as da nova economia, preconiza-se, sob a égide da interatividade, uma renovação da Contabilidade Financeira e sua maior aproximação da Contabilidade Gerencial, com base nos fundamentos da Teoria Contábil.<br>The explosive phenomenon of the Internet, which was unsuspected ten years ago, and is now expanding in an accelerating and involving way in all human activities, has a relevant impact on accounting as well. Interactivity - one characteristic of the new communication form that was inaugurated by the Internet - raises challenges for the Management Accounting System, whose answers, in the form of an interactive view of the enterprise, its assets and its managing process, are expressed in the approach of the Economic Management System. The insufficiency of Financial Accounting to express the reality of the new economy's enterprises in the capital markets is identified. At the same time, we comment on the new opportunities for Financial Accounting, opened up by the presentation of reports with use of Internet resources, based on projects developed by regulatory entities, particularly the IASC. With the increase of interactive accounting communication via Internet and the deepening of the debate about the accounting of enterprises with intellectually intensive assets, like the new economy's ones, a renewal of Financial Accounting and its narrower approach to Management Accounting is expected to occur, under the aegis of interactivity and well-founded on Accounting Theory