irinotecan - topoisomerase poison
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Irinotecan
Camptosar
Topoisomerase I Poison
Adam Corey, Ashley Moody, Charlotte Wells, Sarah Miller Hendricks
March 4, 2014
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Names8
• Generic: Irinotecan CPT-11
• Brand: Camptosar
Classifications
• Antineoplastic agent
• Topoisomerase I Inhibitor
• Camptothecin analog
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Camptothecin7
• Irinotecan is an analog of Camptothecinwhich comes from the Chinese TreeCamptotheca acuminata
• Camptothecins are anticancer drugs thatspecifically target DNA topoisomerase I(Topo I)
Camptothecin Irinotecan
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History7
• 1983-Irinotecan first synthesized in Japan• 1996-Fast-track approval for the treatment of metastatic
colorectal cancer that has recurred or progressedafter therapy with 5 fluorouracil (5-FU)
• 1998-Full FDA approval as second-line therapy for patients
with metastatic colorectal cancer• 2000-FDA approval for irinotecan as first-line therapy for
patients with metastatic colorectal cancer incombination with 5 fluorouracil/leucovorin (5- FU/LV)
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Primary Indications8
• Metastatic colorectal cancer
First-line therapy (in combination with 5-fluorouracil andleucovorin)
In patients whose disease has recurred/progressed afterinitial 5-fluorouracil-based therapy
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Administration9
• Monotherapy
Weekly=125 mg/m2 via IV infusion over 90 minutes
OR
Every 3 weeks= 350 mg/m2 via IV infusion over 30-90 minutes
• Combination Therapy
6 week cycle with infusional 5-FU and leucovorin=180 mg/m2 IV infusion on
days 1, 15, and 29
OR
6 week cycle with bolus 5-FU and leucovorin=125 mg/m2 on days 1,8, 15, and22
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Requirements for the Replisome inDNA Replication5
• 1. primer synthesis
• 2. replicative synthe
• 3. primer removal,replacement (nick tand sealing (ligation
• 4. unwinding the temconformation
• 5. topological relief
• 6. excision repair
Courtesy of Dr. Singleton—ilam 8,9 (Class 10)
Topo I
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Coil
Supercoil
DNA
Torsional Stress5
• Torsional stress arises from the separation of strands in the DNA double helix
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Human DNA Topoisomerase I (Topo I
Topo I relaxes DNA by nicking then closing one strand of the duplex
One strand of the double helix is cut, the other strand is passed through, andthe cut ends are rejoined.
H DNA T i I (T
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Human DNA Topoisomerase I (Topo
• Topo I cleaves DNA using a covalentTyrosine-DNA intermediate
Tyrosine residue (T-723) attacks and covaleto 5’ phosphate group
3’ end of strand is rotated
Reaction is completed by the religation of thstructure
Enzyme dissociates following religation
• Topo I activity is reversible
• Catalytic activity of Topo I is ATP-independent
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•
Human DNA Topoisomerase I (Topo I)6
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TopoI
Mechanism of Action10,12,13
• Irinotecan converts to SN-38
Carboxylesterase
Primarily in the liver
• S-Phase Specificity Topo I relieves torsional strain
SN-38 prevents religation
Replication fork collides with Topo Icleaved complex
Causes dsDNA breaks
• Accumulation of dsDNA breaksleads to apoptosis
SN-38
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Liver
Mechanism of Action10,12,15 Irinotecan
(CPT-11)
SN-38
Carboxylesterase
Helicase Causes Strai
Topo I
Topo I
SN-38G
UGT1A1
GI Tract
DNA Single Strand Bre
DNA Religation
*28
SN-38
Elimination Replication Fork Collisi
DNA Double Strand Bre
B-Glucuronidase
Diarrhea
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Pregnancy and Lactation3
Pregnancy recommendation
• Limited human data – animal data suggest risk
• Category D: positive evidence of risk
Breastfeeding recommendation:
• Contraindicated
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Common Side Effects8
• Nausea
• Vomiting
• Abdominal pain
• Diarrhea
• Constipation• Anorexia
• Neutropenia
Observed in ≥30% of patients
• Leukopenia
• Anemia
• Asthenia
• Fever
• Body weight decreasing• Alopecia
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BLACK BOX WARNING: DIARRHEA AND MYELOSUPPRESSION8
Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by choli
symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threand should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid
electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe
neutropenia. Interrupt irinotecan hydrochloride injection and reduce subsequent doses if sev
diarrhea occurs.
Severe myelosuppression may occur.
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Lesson on Diarrhea16
Early onset
• Occurs within 24 hours
• Caused by cholinergic medicatedeffects
• Prevented by atropine
Late onset
• Occurs after 24 hours (6-11days average)
• Metabolically induced
• Treated with loperamide
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Image from Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management.16
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• Glucuronidated in the liver t
• Inactive metabolite is excretintestine via bile
• Deconjugated in the intestinglucuronidase converting baactive metabolite
• Results in mucosal damage
• Treated with loperamide
Cause of delayed diarr
Image from Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management.16
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Pharmacogenomic Research11,14
• Homozygous for UGT1A1*28 allele
• Lower UGT1A1 expression known as Gilbert’ssyndrome
• Decreased SN-38 glucuronidation
• Predictive factor for toxicities especiallyneutropenia
Image from Polymorphisms that affect irinotecan therapy: http://www.nature.com/nrc/journal/v1/n2/fig_tab/nrc1101-099a_F6.html
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Take Home Points• Irinotecan is a Topo I Poison used for metastatic colorectal cancer
Semisynthetic analog of Camptothecin Activated into SN-38 by Carboxylesterases
• S-Phase Specificity
Topo I relieves torsional stress caused by helicase during DNAreplication
Inhibits Topo1 Religation leading to dsDNA breaks and apoptosis
• Clinical Notes Not recommended for pregnant or breastfeeding women
Black Box Warning: severe diarrhea and myelosuppression
Pharmacogenomics: UGT1A1*28 allele greater risk for neutropenia
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References1. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Figure 5 -25, The rev
reaction catalyzed by a eucaryotic DNA topoisomerase I enzyme.
2. Albertine J. Dressel, Johannes C. van der Mijn, IJke J. Aalders, Rico N.P.M. Rinkel, Hans J. van der Vliet . Irinotecan-Induced Dysarthr
2012 Jan-Apr; 5(1): 47 –51.
3. Briggs, Gerald G.; Freeman, Roger K.; Yaffe, Sumner J. Irinotecan. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and
Lippincott Williams & Wilkins. 2011
4. Berg J, Tymoczko J, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Figure 27.22, Topoisomerase I Mechanism.
5. Berg J, Tymoczko J, Stryer L. Biochemistry: A Short Course. New York: W.H. Freeman; 2012: 602
6. Irinotecan. Clinical Key Available at https://www.clinicalkey.com/). Accessed February, 18, 2014
7. Micromedex Healthcare Series. DRUGDEX System. Greenwood Village, CO: Truven Health Analytics, 2013. http://www.micromedexs
Accessed January 30, 2014.
8. Irinotecan (Rx) – Camptosar, Dosing Forms and Strengths. Medscape. Available at http://reference.medscape.com/drug/camptosar-iri
2014. Accessed February 13, 2014.
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References
9. Kawato Y, Aonuma M, Hirota Y, et al. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antihum
11. Cancer Res. 1991;51:4187-4191.
10. O’Dwyer P, Catalano R. Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arriv
Therapy. JCO October 1, 2006 vol. 24 no. 28 4534-4538. doi: 10.1200/JCO.2006.07.3031
11. Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Bi
2010;17(5):421-433.
12. Rivory L. New drugs for colorectal cancer - mechanisms of action. Australian Prescriber. 2002;25(5):108-110.
13. Rouits E, Boisdron-Celle M, Dumont A, Guerin O, Morel A and Gamelin, E. Relevance of Different UGT1A1 Polymorphisms in Irinot
Toxicity. Clin Cancer Res August 1, 2004 10; 515. doi: 10.1158/1078-0432.CCR-03-0548
14. Saltz L. Clinical use of irinotecan: Current status and future considerations. The Oncologist. 1997;2:402-409.
15. Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther A
2010 January; 2(1): 51 –63. doi: 10.1177/1758834009355164