Modifying SN-38 To Lower Toxicity and Dosage of Irinotecan Administered

Irinotecan, a chemotherapy prodrug developed in Japan and approved for medical use in the US in 1996, is used specifically to treat colon cancer, rectal cancer, and small cell lung cancer. Some side effects of irinotecan include thrombocytopenia, kidney failure, dehydration, diarrhea, vomiting, neutropenia, infections of blood and lungs (sepsis, pneumonia), among others. Many of these significant issues are direct results of the reactivation of its active form, SN-38, in the gut. This compound inhibits the replication of cancer cells by blocking topoisomerase 1, thus obstructing the repair of DNA. Although the β-Glucuronidase (GUS) enzymes that reactivate it are vital, and hence cannot be entirely removed, a way to inhibit GUS enzymes to prevent this conversion from SN-38G would significantly improve the treatment of patients. This research project explores the possibility of decreasing the toxicity of SN-38, and thus minimizing the extreme side effects faced by patients.