Irinotecan
Encyclopedia
Irinotecan is a drug used for the treatment of cancer.
Irinotecan prevents DNA from unwinding by inhibition
of topoisomerase 1
. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin
.
Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI
, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan.
Irinotecan received accelerated approval by the U.S. Food and Drug Administration (FDA) in 1996 and full approval in 1998. During development, it was known as CPT-11.
, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation
by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1
). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.
or Lomotil
with the first loose bowel movement.
counts in the blood, in particular the neutrophils. The patient may experience a period of neutropenia
(a clinically significant decrease of neutrophils in the blood) while the bone marrow increases white cell production to compensate.
. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.
In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.
In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics
recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses. Irinotecan is one of the first widely-used chemotherapy agents that is dosed according to the recipient's genotype.
Irinotecan prevents DNA from unwinding by inhibition
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of topoisomerase 1
Type I topoisomerase
Type I topoisomerases cut one strand of double-stranded DNA, relax the strand, and reanneal the strands. They are further subdivided into two structurally and mechanistically distinct topoisomerases: type IA and type IB....
. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin
Camptothecin
Camptothecin is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I . It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata , a tree native to...
.
Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI
FOLFIRI
FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer. It is made up of the following drugs:* FOL – folinic acid , a vitamin B derivative used as a "rescue" drug for high doses of the drug methotrexate and that modulates/potentiates/reduces the side effects of fluorouracil;* F – ...
, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan.
Irinotecan received accelerated approval by the U.S. Food and Drug Administration (FDA) in 1996 and full approval in 1998. During development, it was known as CPT-11.
Mechanism
Irinotecan is activated by hydrolysis to SN-38SN-38
SN-38 is the active metabolite of irinotecan ; it is 200 times more active than irinotecan itself.SN38 is metabolized via glucoronidation by UGT1A1....
, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1
UGT1A1
UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.UGT-1A is a uridine diphosphate glucuronyltransferase , an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and...
). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.
Side-effects
The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune system.Diarrhea
Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamideLoperamide
Loperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...
or Lomotil
Lomotil
The drug combination diphenoxylate/atropine is a popular oral anti-diarrheal in the United States, manufactured by Pfizer. Its UK BAN generic name is co-phenotrope....
with the first loose bowel movement.
Immunosuppression
The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered white blood cellWhite blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
counts in the blood, in particular the neutrophils. The patient may experience a period of neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
(a clinically significant decrease of neutrophils in the blood) while the bone marrow increases white cell production to compensate.
Pharmacogenomics
Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.*28 variant patients
People with variants of the UGT1A1 called TA7, also known as the "*28 variant", express fewer UGT1A1 enzymes in their liver and often suffer from Gilbert's syndromeGilbert's syndrome
Gilbert's syndrome , often shortened to GS, also called Gilbert-Meulengracht syndrome, is the most common hereditary cause of increased bilirubin and is found in up to 5% of the population...
. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.
In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.
In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics
Pharmacogenomics
Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity...
recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses. Irinotecan is one of the first widely-used chemotherapy agents that is dosed according to the recipient's genotype.
See also
- CamptothecinCamptothecinCamptothecin is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I . It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata , a tree native to...
- TopotecanTopotecanTopotecan hydrochloride is a chemotherapy agent that is a topoisomerase I inhibitor. It is the water-soluble derivative of camptothecin...
(Hycamtin) - PharmacogenomicsPharmacogenomicsPharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity...
- NK012NK012NK012 is a 'nanodevice' formulation of SN-38 . NK012 is an SN-38-releasing nanodevice constructed by covalently attaching SN-38 to the block copolymer PEG-PGlu, followed by self-assembly of amphiphilic block copolymers in aqueous media....
, a nanodevice formulation of SN-38SN-38SN-38 is the active metabolite of irinotecan ; it is 200 times more active than irinotecan itself.SN38 is metabolized via glucoronidation by UGT1A1....
an irinotecan metabolite