ClassificationThis section has been translated automatically.
Irinotecan, like topotecan, is a semi-synthetic derivative of campothecin, an alkaloid extracted from fruits, leaves and the wood of Camptotheca acuminata . It is used as a cytostatic drug in chemotherapy. Irinotecan itself is a prodrug. It is converted into the active and more lipophilic active form mainly in the liver by a carboxyesterase by splitting off the carbamate group. Irinotecan inhibits the enzyme topoisomerase I(topoisomerase inhibitor).
Pharmacodynamics (Effect)This section has been translated automatically.
Type I topoisomerases relax DNA, transforming superhelical DNA into relaxed DNA by reversibly cleaving one strand of duplex DNA. This creates the prerequisite for reading, i.e. transcription of the DNA. After successful DNA replication, the DNA gap is closed again. Type I topisomerases reversibly cleave only one strand of DNA at a time.
Topoisomerase inhibitors I allow DNA cleavage, stabilize the topoisomerase-DNA complex, and prevent the enzyme from closing the cleavage site again. Thus, DNA strand breakage remains to occur and the cell is driven into apoptosis. Topotecan as topoisomerase inhibitor I exerts the strongest antineoplastic activity in S phase (Brogden RN et al 1998).
Note: The type II topoisomerases act in an ATP-dependent manner. They are able to separate both DNA strands.
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IndicationThis section has been translated automatically.
Metastatic colorectal cancer
Primary treatment (first line): Irinotecan is used for first line treatment of metastatic colon cancer in combination with 5-fluorouracil (5-FU) and folinic acid.
Second line treatment: Irinotecan is used for second line treatment of metastatic colon cancer that has not responded or has responded inadequately to primary treatment with 5-FU and folinic acid.
Experimental data are available:
- In adults: cervical carcinoma, esophageal carcinoma, gastric carcinoma, lung carcinomas, mesothelioma, pancreatic carcinoma, bile duct carcinoma.
- In children and adolescents for: Ewing's sarcoma, neuroblastoma, rhabdomyosarcoma, PNET, Wilms' tumor as well as various brain tumors (ependymal tumor). Brain tumors (ependymoma, medulloblastoma, malignant glioma, glioblastoma, PNET).
- Combination of cetuximab plus irinotecan in metastatic colorectal carcinoma (Horie Y et al. 2015).
- Combination of docetaxel and irinotecan in metastatic melanoma (Tas F et al. 2003).
- Combination of irinotecan and carboplatin in advanced non-small cell lung cancer (Takeda K et al. 2002).
Pregnancy/nursing periodThis section has been translated automatically.
Irinotecan is contraindicated during lactation (see section 4.3). Although it is not known whether irinotecan passes into human breast milk, it is recommended to stop breastfeeding before starting therapy.
Fertility: No effects on male or female fertility have been observed in reproductive toxicology studies in rats. However, irinotecan, like other cytotoxic drugs, is genotoxic and effects on fertility, including male fertility, cannot be excluded.
Undesirable effectsThis section has been translated automatically.
Irinotecan is characterised by severe diarrhoea (late diarrhoea), which only sets in after 5 days. These are treated with loperamide. In addition, irinotecan can trigger a "cholinergic syndrome" (inhibition of acetylcholinesterase) within 24 hours. This is characterised byflushing, diarrhoea, abdominal pain, sweating, miosis and increased tears and saliva flow (therapy with atropine).
Other possible adverse effects are myelosuppression (manifested in neutropenia, anemia and thrombopenia), alopecia, liver damage (elevation of transaminases, hyperbilirubinemia, jaundice to liver failure), Kidney damage (increase in creatinine, sometimes renal failure, especially with simultaneous fluid loss through diarrhoea), hypersensitivity (hypersensitivity, allergic reaction), colitis, ileus (inflammation and obstruction of the bowel).
LiteratureThis section has been translated automatically.
- Bailly C (2019) Irinotecan: 25 years of cancer treatment. Pharmacol Res 148:104398.
- Brogden RN et al (1998) Topotecan. A review of its potential in advanced ovarian cancer. Drugs, 56: 709-23
- de Man FM et al (2018) Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Clin Pharmacokinet 57:1229-1254.
- European Medicines Agency: http://www.ema.europa.eu/
- Hahn RZ et al (2019) Pharmacokinetic and Pharmacogenetic Markers of Irinotecan Toxicity. Curr Med Chem 26:2085-2107.
- Horie Y et al (2015) Predictability of antitumor efficacy of cetuximab plus irinotecan based on skin rash severity according to observation period in patients with metastatic colorectal cancer following failure of fluorouracil, irinotecan and oxaliplatin. Mol Clin Oncol 3:1029-1034.
- Mohammad AS et al (2018) Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer. Pharm Res 35:31.
- Takeda K et al (2002) Phase II study of irinotecan and carboplatin for advanced non-small cell lung cancer. Lung cancer 38:303-308.
- Tas F et al (2003) Combination chemotherapy with docetaxel and irinotecan in metastatic malignant melanoma. Clin Oncol (R Coll Radiol) 15:132-135.
- Tsavaris N et al (2003): Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination. A randomized study. Cancer chemother Pharmacol 52: 514-519.