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

结直肠癌（CRC）是德国第二大诊断癌症，每年导致30000人死亡。一般来说，CRC的发展是环境因素和遗传易感性之间相互作用的结果。细胞防御系统在潜在致癌的外源性物质的解毒中起着至关重要的作用，因此在癌症预防中也起着至关重要的作用。UDP-葡萄糖醛酸转移酶（UGT）作为细胞防御机制的一部分，催化致癌物和药物等异生物质物质的解毒。伊立替康根据临床情况，单药治疗或与其他细胞生长抑制剂（FOLFIRI）联合治疗转移性CRC。20-30%的治疗患者出现严重副作用，如腹泻和白细胞减少症（高达WHO 4级），代表剂量限制性毒性，影响伊立替康的治疗和治愈潜力。普遍表达的羧酸酯酶催化伊立替康转化为其活化但毒性更高的代谢产物SN 38。UGT的葡萄糖醛酸化导致SN 38通过胆汁和尿液灭活和消除。在几项研究中，UGT 1A 1基因启动子突变（UGT 1A 1 *28）与伊立替康治疗期间严重副作用的发生率增加相关。然而，大约50%的携带这种基因型的患者遭受严重的副作用，表明其他因素可能在预测腹泻和白细胞减少症中发挥作用。对105例接受伊立替康治疗的患者进行的基因分型显示，只有UGT 1A 7基因（UGT 1A 7 *3）中3种不同多态性与UGT 1A 1 *28变体的组合才是发生伊立替康毒性的可靠预测因子。在此背景下，我们希望研究SNP介导的葡萄糖醛酸化活性降低是否可以通过适当的无毒UGT 1A诱导剂进行补偿，并可能导致伊立替康相关毒性降低。在本项目中，应分析UGT 1A激活剂咖啡对伊立替康治疗期间副作用发生率和严重程度的影响。因此，使用携带上述UGT 1A单倍型作为转基因的人源化转基因小鼠系。将结果与携带野生型形式的人UGT 1A基因座的第二小鼠系的结果进行比较。此外，应分析咖啡参与伊立替康治疗期间的性别特异性差异，可能为尚未建立的性别特异性治疗策略提供基础。

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.