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

Nucleolar Proteins Suppress Caenorhabditis elegans Innate Immunity by Inhibiting p53/CEP-1

The tumor suppressor p53 has been implicated in multiple functions that play key roles in health and disease, including ribosome biogenesis, control of aging, and cell cycle regulation. A genetic screen for negative regulators of innate immunity in Caenorhabditis elegans led to the identification of a mutation in NOL-6, a nucleolar RNA-associated protein (NRAP), which is involved in ribosome biogenesis and conserved across eukaryotic organisms. Mutation or silencing of NOL-6 and other nucleolar proteins results in an enhanced resistance to bacterial infections. A full-genome microarray analysis on animals with altered immune function due to mutation in nol-6 shows increased transcriptional levels of genes regulated by a p53 homologue, CEP-1. Further studies indicate that the activation of innate immunity by inhibition of nucleolar proteins requires p53/CEP-1 and its transcriptional target SYM-1. Since nucleoli and p53/CEP-1 are conserved, our results reveal an ancient immune mechanism by which the nucleolus may regulate immune responses against bacterial pathogens

Tumors of the Chest Wall

Primary tumors of the chest wall are uncommon. Chest wall tumors, whether malignant or benign,are classified as primary or secondary (metastatic).The most common benign tumors are osteochondromas and chondromas. The most common malignant chest wall tumors are sarcomas. Most primary tumors originate in the bones or muscles of the chest wall, though they can also arise from nerves and vessels. Less than half of malignant chest wall tumors are primary. Secondary tumors originate elsewhere in the body and spread (metastasize) to the chest wall. The most frequent secondary tumors of the chest wall spread from primary breast and lung cancer. In fact, they can either locally extend to the chest wall, or metastasize to it. Furthermore, other tumors that are not unfrequently spread to the pleura include those originating from ovary, kidney, uterus, head and neck, and testis. Therefore, almost all secondary tumors are malignant. Most chest wall tumors found in children are primary, while most found in adults are secondary . It is often difficult to make an accurate presurgical diagnosis and differentiate benign from malignant tumors. Most patients with primary chest wall tumor receive surgical biopsy or radical surgical resection