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onthehorizononthehorizononthehorizononthehorizononthehorizononthehorizononthehorizonthe chemotherapyclockEveryone has an internal clock, a genetictimepiece that controls a broad range ofmetabolic, cellular, physiological and behavioralactivities. Understanding which genescontrol the variations in these daily activitiescould lead not only to new cancer therapies,but also to the best time of day to applythose therapies.The concept is simple: If you know whena person is more sensitive to chemotherapy- that is, when less of a toxic chemical isneeded to achieve the same cancer-fightingeffect with fewer physical side effects - drugtherapies can be directed accordingly. Theresult would be to more carefully administertherapies to the time of greater tolerance.Marina Antoch, Ph.D., Cancer Biology, isamong a group of researchers at theCleveland Clinic Lerner Research Instituteand the Howard Hughes Medical Institutewho reported on how the internal clock controlsthe response to one of the widely usedchemotherapeutic drugs - cyclophosphamide.The results were published earlier thisyear in the Proceedings of the NationalAcademy of Sciences.“Within the last eight years, the genesthat govern the circadian system have beenidentified and explored and we’ve madetremendous gains in the area,” saysDr. Antoch. “This is the first link establishedbetween the molecular mechanics of theinternal body clock and the effect of therapeuticdrugs.”Dr. Antoch and her colleagues also willbe investigating biological and medicalpossibilities for “re-setting” a person’s internalclock so that the body will think it’sreceiving therapy during the most effectivepart of its daily rhythm.Turning Off IBD TriggersInflammatory bowel disease (IBD) affects morethan one million Americans. During inflammatoryflare-ups, a hallmark symptom of IBD,erosion of the inner lining of the intestineoccurs, causing bleeding, diarrhea, fever andabdominal pain.Cleveland Clinic researchers Scott Strong,M.D., and Carol de la Motte, Ph.D., with theDepartment of Colorectal Surgery and theDepartment of Pathobiology, want to find a wayto stop the inflammation and erosion processassociated with IBD. To do this, they are focusingon how cell mechanisms within the bowelwork and how they trigger IBD symptoms.Researchers believe that environmentaltriggers, including microbiological agents andviruses, begin the process of inflammation andkeep it going in the intestine of patients whoare genetically susceptible to IBD.Dr. Strong’s team has found that when avirus infects muscle cells in the intestine,the cells will make big, long cables of acompound called hyaluronan. This compoundis essential for the body’s ability to repair itselfand is found in the joints, liver, skin, eyesand intestine.“When these long, complex cables of hyaluronanare produced, white blood cells willcome and sit on them,” says Dr. Strong. “Thewhite blood cells then become activated,releasing their own chemicals, attacking anderoding the interior lining of the intestine.”Although much more research is needed tofully understand this cell mechanism, Clinicresearchers are looking at several options thatwould essentially prevent IBD flare-ups fromoccurring. These options include halting theexcessive production of hyaluronan or promotingthe breakdown of hyaluronan. Anotherpossible option is to interfere with the whiteblood cells that attach to the hyaluronan,preventing the release of chemicals thatperpetuate inflammation.The long green hyaluronan cables attract whiteblood cells, shown here as the round blue balls,which then attach themselves to the cables.42 cleveland clinic magazine