Irinotecan

MRP1 (ABCC1) Glucuronides and sulfate conjugates of steroid hormones and bile salts, colchicine, doxorubicin, daunorubicin, epirubicin, folate, irinotecan, methotrexate, pacitaxel, vinblastine, vincristine, and others... 

BCRP (ABCG2) Cisplatin, folate, methotrexate, mitoxantrone, topotecan, irinotecan, steroids (cholesterol, testosterone, progesterone), certain chlorophyll metabolites, and others... 

Camptothecins (irinotecan, topotecan) are derived from the bark of the Chinese tree Xi Shu (Camptotheca accuminata). They inhibit topoisomerase I thus effecting double strand breaks. Unwanted effects include diarrhea and reversible bone marrow depression. 

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

Irinotecan (CPT-11) is approved for colorectal tumors. It is given by intravenous infusion. The most severe side effect is diarrhea, which can be severe and needs to be treated by a physician. Temporary liver dysfunction is generally asymptomatic. The other side effects are the same as those produced by topotecan. 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

The clinical trial that resulted in FDA approval of bevacizumab (February 2004) was a randomized, double-blind, phase III study in which bevacizumab was administered in combination with bolus-IFL (irinotecan, 5FU, leucovorin) chemotherapy as first-line therapy for previously untreated metastatic colorectal cancer [3]. Median survival was increased from 15.6 months in the bolus-IFL + placebo arm to 20.3 months in the bolus-IFL + bevacizumab arm. 

Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovor-in for metastatic colorectal cancer. N Engl J Med 350 2335-2342... 

Ci()H2()N2 4897-50-1) see Irinotecan 4-piperidinopiperidine-4-carboxamide see under 4-carbamoyl-4-piperidinopiperidine... 

Ion transfer, 14 (1977) 1 Irinotecan, anticancer agent, 34 (1997) 68 Isothermal titration calorimetry, in drug design, 38 (2001) 309... 

CAV, cyclophosphamide, doxorubicin, vincristine EC, etoposide carboplatin EP, etoposide cisplatin IC, irinotecan, cisplatin. See Table 87M for doses and schedules. 

Platinum regimens are also the treatment of choice in extensive disease, and many studies have failed to show superiority to the EP regimen as first-line treatment. A combination of irinotecan and cisplatin in one Japanese study demonstrated an increased median survival time by approximately 3 months... 

Triple -drug therapy consisting of 5-fluorouracil and leucovorin with oxaliplatin or irinotecan improves survival compared with 5-fluorouracil plus leucovorin alone and is... 

FOLFIRI Irinotecan 1 80 mg/m2 IV day 1 Folinic acid (leucovorin) 200 mg/m2 IV day 1 5-Fluorouracil 400-500 mg/m2 IV bolus, after folinic acid then 2400-3000 mg/m2 of 5-fluorouracil IV over 46 hours Repeat every 14 days... 

CAPIRI Capecitabine 1 000 mg/m2 twice a day for 14 days Irinotecan 100 mg/m2 IV days 1 and 8 Repeat every 22 days... 

FOLFIRI Folinic acid (leucovorin) + 5-fluorouracil + Irinotecan given as combined IV boluses and continuous infusions... 

CAPIRI Capecitabine + Irinotecan given as oral therapy and IV boluses... 

Irinotecan Topoisomerase inhibitor that forms a complex with Dose-limiting... 

The dose of capecitabine begins at 1250 mg/m2 twice a day when used by itself lower doses are used often when it is given in combination with irinotecan or oxaliplatin or in patients with renal insufficiency. The dose should be taken on a full stomach with breakfast and dinner. Capecitabine administered with warfarin can result in significant increases in the patient s INR and requires close monitoring to prevent bleeding. The convenience of oral administration and an improvement in toxicity make capecitabine a useful alternative to IV 5-FU both by itself and incorporated into other regimens used in colon cancer. 

Irinotecan (Camptosar ) is a topoisomerase I inhibitor that forms a complex with the covalently bound DNA topoisomerase... 

Similar to 5-FU, there is a polymorphism associated with irinotecan toxicity. UDP-glucuronosyltransferase (UGT1A1) is an enzyme responsible for the glucuronidation of SN-38 to inactive metabolites, and reduced or deficient levels of this enzyme correlate with irinotecan-induced diarrhea and neutropenia.39 Recently the FDA approved a blood test that detects variations in this gene. This test will assist health care providers in predicting which patients may develop severe toxicities from normal doses of irinotecan and can be ordered prior to patients receiving irinotecan. binotecan is administered as an IV bolus over 60 to 90 minutes in a variety dosing schedules. 

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