title: Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer.
abstract: Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy.
authors.affiliation: Ken-ichi Fujita, Yasutsuna Sasaki, Institute of Molecular Oncology, Showa University, Tokyo 1428555, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Ken-ichi Fujita, Yasutsuna Sasaki, Institute of Molecular Oncology, Showa University, Tokyo 1428555, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: Ken-ichi Fujita, Yasutsuna Sasaki, Institute of Molecular Oncology, Showa University, Tokyo 1428555, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Ken-ichi Fujita, Yasutsuna Sasaki, Institute of Molecular Oncology, Showa University, Tokyo 1428555, Japan.
authors.forename: Yasutsuna
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001711:Biotransformation / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D054796:Drug Dosage Calculations; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D009362:Neoplasm Metastasis; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin
keywords: Dosing; Irinotecan; Metastatic colorectal cancer; Personalized chemotherapy; Severe renal failure; Survival advantage