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

Sentinel lymph node biopsy for squamous cell carcinoma of the anal canal

The definitive version is available at www.blackwell-synergy.comBackground: The current Trans-Tasman Radiation Oncology Group (TROG) protocol for T1 and T2 anal cancers is combination chemotherapy and radiotherapy excluding the inguinal region from the field. Several centres worldwide irradiate both inguinal regions as there is a small incidence of involvement with early stage tumours. The presence of inguinal lymph node metastases is not accurately detected using clinical and most radiological assessment modalities. We have developed a method of sampling the sentinel node in the groin using established node mapping techniques. Methods: A combination of radio-labelled Antimony Sulphide and Patent Blue dye injected around the anal cancer enable identification of the sentinel node in the groin, using a gamma probe and direct visualization of the blue node. Results: This technique has been used in four patients. A groin sentinel node was identified and removed in three of these, with pathological assessment excluding metastatic disease in the inguinal region. The fourth patient had a sentinel node mapped to a meso-rectal node. This was not sampled. Conclusions: The application of this effective technique will allow accurate staging of anal cancers to better plan future treatment regimes.Philippa Rabbitt, Nimilan Pathma-Nathan, Trevor Collinson, Peter Hewett and Nicholas Riege