Irinotecan - Topoisomerase Poison

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Irinotecan

Camptosar

Topoisomerase I Poison

Adam Corey, Ashley Moody, Charlotte Wells, Sarah Miller Hendricks

March 4, 2014



Names8

• Generic: Irinotecan CPT-11

• Brand: Camptosar

Classifications

• Antineoplastic agent

• Topoisomerase I Inhibitor

• Camptothecin analog



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



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)



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



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



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



Coil

Supercoil

DNA

Torsional Stress5

• Torsional stress arises from the separation of strands in the DNA double helix



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



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



•

Human DNA Topoisomerase I (Topo I)6



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



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



Pregnancy and Lactation3

Pregnancy recommendation

• Limited human data – animal data suggest risk

• Category D: positive evidence of risk

Breastfeeding recommendation:

• Contraindicated



Common Side Effects8

• Nausea

• Vomiting

• Abdominal pain

• Diarrhea

• Constipation• Anorexia

• Neutropenia

Observed in ≥30% of patients

• Leukopenia

• Anemia

• Asthenia

• Fever

• Body weight decreasing• Alopecia



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.



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



Image from Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management.16



• 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



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



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



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.



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

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