Ttoxicity analyses and therapeutic modification of the anti-cancer drug camptothecin

• Applicant: Professor Dr. Christian Strassburg
• Subject Area: Gastroenterology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282635917

Colorectal cancer (CRC) is he second most diagnosed cancer in Germany leading to death of 30000 people per year. Generally, development of CRC is the outcome of interactions between environmental factors and genetic predisposition. The cellular defence system plays an essential role in the detoxification of potentially carcinogenic xenobiotics and consequently in cancer prevention. UDP-glucuronosyltransferases (UGT), as a part of the cellular defence mechanisms, catalyze the detoxification of xenobiotic substances like carcinogens and drugs.Irinotecan is used, depending on the clinical context, in a monotherapy or in combination with other cytostatic agents (FOLFIRI) for the treatment of metastatic CRC. 20-30% of the treated patients suffer from serious side effects like diarrhoea and leucopenia (up to WHO grade 4) representing the dosis limiting toxicity which affects the therapeutic and curative potential of irinotecan. Ubiquitous expressed carboxylesterases catalyze the conversion of irinotecan to its activated but also more toxic metabolite SN38. Glucuronidation by UGTs leads to inactivation and elimination of SN38 via bile and urine. In several studies, a promoter mutation in the UGT1A1 gene (UGT1A1*28) was associated with increased occurrence of serious side effects during irinotecan therapy. However, approximately 50% of the patients carrying this genotype suffered from serious side effects indicating that further factors may play a role in the prediction of diarrhoea and leucopenia. Genotyping of 105 irinotecan treated patients revealed that only the combination of 3 different polymorphisms in the UGT1A7 gene (UGT1A7*3) together with the UGT1A1*28 variant is a reliable predictor for the occurrence of irinotecan-toxocity. Against this background we want to investigate if the SNP-mediated reduced glucuronidation activity can be compensated by appropriate, non-toxic UGT1A-inducers and potentially leads to reduction of irinotecan associated toxicity. Within this project, the effects of the UGT1A-activator coffee on the occurrence and the severity of side effects during irinotecan-treatment should be analyzed. Therefore, a humanized transgenic mouse line is used which carries the above mentioned UGT1A-haplotype as a transgene. The results are compared to those of a second mouse line which carries the human UGT1A gene locus in the wild type form. Additionally, gender specific differences during a coffee attended irinotecan-therapy should be analyzed potentially offering fundamentals for not yet established gender specific therapeutic strategies.

• DFG Programme: Research Grants