Topoisomerase inhibitors colorectal cancer

Saif MW, Diasio RB. Edotecarin a novel topoisomerase I inhibitor. Clin. Colorectal. Cancer. 2005 May 5(l) 27-36. 

Rothenberg ML, Blanke CD. Topoisomerase I inhibitors in the treatment of colorectal cancer. Semin Oncol 1999 26(6) 632-639. 

Irinotecan is an analogue of camptothecin, a topoisomerase I inhibitor that is used for the treatment of advanced colorectal cancer and a few other solid tumors. Irinotecan is first converted to an active metabolite, SN-38, which is further conjugated into the inactive SN-38 glucuronide (SN-38 G), mainly by UGTIAI, and then eliminated via the bile. A common dinucleotide (TA) repeat polymorphism (containing 5, 6, 7, or 8 copies of TA repeat) has been identified in the UGTIAI promoter TATA box. 

Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracil-based therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin. Myelosuppression and diarrhea are the two most common adverse events. There are two forms of diarrhea an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2-10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases. 

Doxorubicin is a nonspecific inhibitor of topoiso-merase I and II. Topotecan and irinotecan selectively inhibit topoisomerase I, an enzyme required for DNA replication. These agents have clinical efficacy in relapsed ovarian and colorectal cancer, respectively. Dose limiting toxicity is bone marrow depression and, in the case of irinotecan, delayed diarrhoea. Administration of irinotecan may be complicated by an acute cholinergic reaction, reversible by administering atropine s.c. 

Another dual inhibitor of topoisomerase I and topoisomerase II is XR 5000 (N-2-[(dimethylamino)ethyl]acri-acridine-4-carboxamine). Its cytotoxicity was not affected by the presence of P-glycoprotein, and it seems to be a promising candidate, even in highly resistant tumor cells. However, neither complete nor partial remission was observed during a phase II trial in 20 patients with advanced or metastatic colorectal cancer (21). 

Irinotecan, an antineoplastic-prodrug, is widely used for the treatment of colorectal, lung and other cancers, and is one of model pharmaceuticals for personalized medicine. The active metabolite, SN-38, is a topoisomerase I inhibitor generated by hydrolysis of irinotecan by carboxylesterases. SN-38 is subsequently glucuronidated... 

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