"In a small phase I clinical trial Johns Hopkins Kimmel Cancer Center researchers say they show for the first time that the experimental drug guadecitabine SGI is safe in combination with the chemotherapy drug irinotecan and may overcome resistance to irinotecan in patients with metastatic colorectal cancer. Results of the study are expected to be presented April  at the American Association for Cancer Research AACR Annual Meeting  in New Orleans abstract CT.  Guadecitabine works to reverse a socalled epigenetic change in cancer cells known as methylation which may alter genetic activity in cells in a way that can block the action of tumorsuppressing genes pushing cells to become cancerous and resistant to therapy. By reversing this change in cancer cells the drug restores cancer cells vulnerability to drugs such as irinotecan. The clinical trial included  patients with metastatic colorectal cancer who had been treated previously with irinotecan and whose disease was progressing. The patients were divided into four groups each receiving different doses of guadecitabine in combination with irinotecan over an average period of four months. During the study  patients had at least one imaging scan to retest the extent and location of their cancers  with  patients experiencing stable disease  for more than the fourmonth period on average and one patient experiencing a partial response to the treatment measured as at least a  percent reduction in the size of the tumors. Although the studys main purpose was to test the safety rather than the effectiveness of guadecitabine doses we were very happy to see some patients who benefited from the combination of the therapies for many months to more than a year says Nilofer Azad M.D. professor of oncology at the Johns Hopkins University School of Medicine. The study also showed signs that guadecitabine reduced methylation among the cancer cells. We did see that giving a higher dose of the drug seemed to produce a better methylation response among patients says Valerie Lee M.D. a fellow at the Johns Hopkins Kimmel Cancer Center. However it seemed that patients were responding at all levels of the drug. Among the side effects of the combined treatment  patients experienced neutropenia a low count of the infectionfighting white blood cells called neutrophils five patients with neutropenia had fevers three patients became anemic and two patients developed thrombocytopenia a lowered count of bloodclotting platelets. Other side effects included diarrhea three patients fatigue two patients and dehydration two patients. There was one death during the study possibly resulting from febrile neutropenia caused by the treatment. The current study was based on previous studies in the laboratory of Nita Ahuja M.D. director of the Sarcoma and Peritoneal Surface Malignancy Program and professor of surgery at the Johns Hopkins University School of Medicine which showed that guadecitabine limited the growth of colorectal cancer cell lines when combined with irinotecan says Azad.  The drug combination is being tested in an ongoing phase II clinical trial NCT in a larger group of metastatic colorectal cancer patients at multiple institutions to determine the effectiveness of the dual therapy compared with chemotherapy regimens that do not include guadecitabine says Azad. Scientists leading the new study will also look for biomarkers in patients that could help determine which of them are most likely to benefit from guadecitabine and irinotecan. Lee says the research team will measure the amount of methylation in patients cells when they begin their treatment and the presence of genes associated with irinotecan resistance among other possible biomarkers. In  there were more than  people in the U.S. diagnosed with colon cancers. Fiveyear survival rates among people with localized colon cancers are more than  percent but they are only  percent in those with metastatic cancer.  Guadecitabine is an experimental drug that has not been approved for use by the U.S. Food and Drug Administration. It is manufactured by Astex Pharmaceuticals a supporter of the Johns Hopkinsled study. The research was also supported by the Van Andel Research Institute SUCAACR Epigenetics Dream Team. Other scientists who contributed to the research include Judy Wang Anup Sharma Zachary Kerner Stephen Baylin Ellen Lilly and Thomas Brown from Johns Hopkins Anthony El Khoueiry from the University of Southern California Henk Verheul and Elske Gootjes from Vrije Universiteit in the Netherlands and Peter Jones from the Van Andel Research Institute."