Adv Exp Med Biol
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Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. ⋯ Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower. Table 1 summarizes metastatic breast cancer response rates to single-agent systemic therapy.
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Alveolar hypoxia occurs during ascent to high altitude and is also observed in patients with ARDS and acute hypoxemic respiratory failure, in which alveolar flooding is associated with a decrease in edema fluid clearance and increased mortality. The mechanisms that lead to the impairment of alveolar fluid clearance are not completely understood. Alveolar fluid reabsorption is accomplished mostly by active Na+ transport across the alveolar epithelium which creates an osmotic gradient responsible for the clearance of lung edema from the alveolar spaces. ⋯ More prolonged hypoxia causes the ubiquitination and degradation of Na,K-ATPase. Thus, methods that counterbalance the inhibition of edema clearance during hypoxia and improve the lung's ability to clear pulmonary edema are needed. As such, a better understanding of the mechanisms that increase Na,K-ATPase function, (i.e., activation of dopaminergic or adrenergic receptors, gene transfer) may lead to the development of therapeutic approaches to upregulate the Na-K-ATPase function and increase edema clearance.
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The myocardium is well protected against chronic hypoxia. In chronic hypoxia stroke volume falls both at rest and on exercise. The fall in stroke volume is associated with reduction in left ventricular dimensions and filling pressure. ⋯ The relative importance of different mechanisms which reduce stroke volume probably depends whether hemodynamics are measured at rest or on exercise. Intervention with sildenafil to ameliorate hypoxic pulmonary vasoconstriction is associated with both an increase in exercise capacity and stroke volume in hypoxia. Whether these have a causal association remains to be demonstrated.
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The cytotoxic RNase, Onconase (ONC), isolated from amphibian oocytes, was used to study its effect on the radiation response in A549 human NSCLC in vitro and in vivo. In cell culture studies, we found that ONC increased the radiation response by ONC-induced inhibition of O2 consumption (QO2). The occurrence of apoptosis was increased by ONC and was dependent on dosages and time exposure (measured by a Tunnel in situ cell death detection assay). ⋯ Using a non-invasive DCE-MRI technology, ONC-induced changes of perfusion were observed in A549 tumors. We concluded that the ONC-induced enhancement in tumor oxygenation was mainly due to the reduction in QO2 rather than an increase in tumor blood flow. This investigation suggests important potential clinical uses of ONC for the treatment of NSCLC cancer patients.