Upper gastrointestinal cancer

The group has integrated with the NHS multidisciplinary team and actively recruits to National Cancer Research Network sponsored phase III trials. A protocol for banking tumour samples has been set up to provide the McHugh laboratory with material from which to investigate the role of platinum repair in the outcome of patients been treated for gastro oesophageal and pancreatic cancers. This will provide useful background information for forthcoming investigations into repair and apoptic modulation with hypomethylating agents, and an investigation of the impact of EGFR or carbonic anhydrase inhibitors upon the DNA damage wrought by chemotherapy and its repair.

DNA repair inhibitors

The most important factor in tumour resistance to nitrosoureas and tetrazines is the DNA repair protein 06-methylguanine-DNA methyltransferase (MGMT). MGMT recognises and removes methyl adducts generated in DNA by such agents. The protein is itself destroyed in this reaction and is therefore susceptible to depletion. MGMT is found in all tissues and is therefore an intrinsic resistance factor to these drugs. Levels of expression are largely higher in tumour tissue than in the corresponding normal tissue. Depletion of MGMT by pseudosubstrate guanine analogues might therefore be expected to improve the efficacy of 06 alkylating agent chemotherapy. We have been able to demonstrate this in model systems, and show that the enhanced efficacy is greater than that which can be achieved merely by escalating chemotherapy doses. Patrin-2 is an MGMT inhibitor developed by Cancer Research UK at the Paterson Institute in Manchester. Phase I clinical trials have recently been completed and the phase II programme includes an evaluation of its use in conjunction with Temozolomide in melanoma and colorectal cancer and will be undertaken in Oxford and Manchester. A phase I study is under way in Oxford to investigate the doses of Patrin-2 required to deplete MGMT in patients with prostate and primary CNS cancers.