Research Implicates Altered Gene Expression from Toxic Metabolite of Chemotherapy Agent in Treatment of Colorectal Liver Tumors
A study by a graduate student and a faculty researcher in UH College of Pharmacy suggests a link from an altered toxic metabolite of a chemotherapy agent used in the treatment of colorectal liver cancer to the development of an increasingly common complication known as fatty liver disease.
The research by Pharmaceutics doctoral student Pankajini Mallick and her advisor, Associate Professor Romi Ghose, Ph.D., was presented at the Society of Toxicology 54th Annual Meeting March 22-26 in San Diego. Mallick also was selected to receive a Graduate Student Travel Support Award from the society to present their project at the meeting.
The anticancer drug irinotecan is used in combination with other chemotherapy drugs for treatment of metastatic carcinoma of the colon or rectum or alone when disease has recurred or progressed following initial therapy. In pre-operative chemotherapy, systemic treatment of irinotecan before surgical removal (resection) of colorectal liver tumors is used to reduce the size of tumor(s) and facilitate surgery of initial unresectable liver tumors.
Clinical evidence has revealed that pre-operative chemotherapy with irinotecan in colorectal metastatic liver patients was associated with fatty liver disease (FLD). Covering a broad spectrum of liver disorders, FLD initiates as fat accumulation in the liver (steatosis) due to disrupted lipid homeostasis and typically progresses into steatohepatitis and life-threatening cirrhosis. FLD is a serious complication/impediment to treatment strategies for colorectal liver cancer, as FLD can impair liver function and repair, alter drug metabolism (consequently increasing toxicity risk and reducing effectiveness), and potentially lead to post-operative complications and mortality.
However, the mechanisms involved in development of FLD with irinotecan chemotherapy are largely unknown.
"Irinotecan is metabolized into a potent and toxic metabolite: SN-38," Mallick said. "Our in-vivo studies showed irinotecan-induced steatosis in liver was associated with altered gene expression of enzymes involved in regulation of lipid homeostasis and drug metabolism of irinotecan itself, which indicates SN-38 plays a role in the development of fatty liver disease with irinotecan."