Irinotecan

Camptosar



Topoisomerase I Poison
Adam Corey, Ashley Moody, Charlotte Wells, Sarah Miller Hendricks
March 4, 2014

Objectives
To introduce irinotecan and provide general
information about its classification, history, and
indications for use
To discuss the role of DNA topoisomerase I in
human cells as well as the implications of its
inhibition
To describe the mechanism of action of irinotecan
To reveal potential side effects and black box
warnings associated with the use of irinotecan in
patients
Names
8
Generic: Irinotecan
CPT-11
Brand: Camptosar

Classifications

Antineoplastic agent
Topoisomerase I Inhibitor
Camptothecin analog








Camptothecin
7
Irinotecan is an analog of Camptothecin
which comes from the Chinese Tree
Camptotheca acuminata
Camptothecins are anticancer drugs that
specifically target DNA topoisomerase I
(Topo I)

Camptothecin
Irinotecan
History
7
1983-Irinotecan first synthesized in Japan
1996-Fast-track approval for the treatment of metastatic
colorectal cancer that has recurred or progressed
after 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 in
combination with 5 fluorouracil/leucovorin (5- FU/LV)
Primary Indications
8
Metastatic colorectal cancer

First-line therapy (in combination with 5-fluorouracil and
leucovorin)

In patients whose disease has recurred/progressed after
initial 5-fluorouracil-based therapy
Administration
9
Monotherapy
Weekly=125 mg/m
2
via IV infusion over 90 minutes
OR
Every 3 weeks= 350 mg/m
2
via IV infusion over 30-90 minutes

Combination Therapy
6 week cycle with infusional 5-FU and leucovorin=180 mg/m
2
IV infusion on
days 1, 15, and 29
OR
6 week cycle with bolus 5-FU and leucovorin=125 mg/m
2
on days 1,8, 15, and
22


Requirements for the Replisome in
DNA Replication
5
1. primer synthesis
2. replicative synthesis
3. primer removal,
replacement (nick translation)
and sealing (ligation)
4. unwinding the template
conformation
5. topological relief
6. excision repair
Courtesy of Dr. Singletonilam 8,9 (Class 10)
Topo I

Coil

Supercoil
DNA
Torsional Stress
5
Torsional stress arises from the separation of strands in the DNA double helix
Human DNA Topoisomerase I (Topo I)
4
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, and
the cut ends are rejoined.
Human DNA Topoisomerase I (Topo I)
1
Topo I cleaves DNA using a covalent
Tyrosine-DNA intermediate

Tyrosine residue (T-723) attacks and covalently binds
to 5 phosphate group

3 end of strand is rotated

Reaction is completed by the religation of the cleaved
structure

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 Action
10,12,13
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 I
cleaved complex
Causes dsDNA breaks
Accumulation of dsDNA breaks
leads to apoptosis
SN-38
Irinotecan
Mechanism of Action
10,12,13,15

Helicase
Topo I
SN-38
Liver
Mechanism of Action
10,12,15

Irinotecan
(CPT-11)
SN-38
Carboxylesterase
Helicase Causes Strain
Topo I
Topo I
SN-38G
UGT1A1
GI Tract
DNA Single Strand Break
DNA Religation
*28
SN-38
Elimination
Replication Fork Collision
DNA Double Strand Break
B-Glucuronidase
Diarrhea
Pregnancy and Lactation
3
Pregnancy recommendation
Limited human data animal data suggest risk
Category D: positive evidence of risk
Breastfeeding recommendation:
Contraindicated
Common Side Effects
8
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 MYELOSUPPRESSION
8


Early and late forms of diarrhea can occur. Early diarrhea may be accompanied by cholinergic
symptoms which may be prevented or ameliorated by atropine. Late diarrhea can be life threatening
and should be treated promptly with loperamide. Monitor patients with diarrhea and give fluid and
electrolytes as needed. Institute antibiotic therapy if patients develop ileus, fever, or severe
neutropenia. Interrupt irinotecan hydrochloride injection and reduce subsequent doses if severe
diarrhea occurs.
Severe myelosuppression may occur.
Table from Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management.
16
Lesson on Diarrhea
16
Early onset
Occurs within 24 hours
Caused by cholinergic medicated
effects
Prevented by atropine
Late onset
Occurs after 24 hours (6-11days on
average)
Metabolically induced
Treated with loperamide

Image from Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management.
16
Glucuronidated in the liver to SN-38G
Inactive metabolite is excreted into the
intestine via bile
Deconjugated in the intestine by -
glucuronidase converting back to the
active metabolite
Results in mucosal damage
Treated with loperamide


Cause of delayed diarrhea
Image from Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management.
16
Pharmacogenomic Research
11,14
Homozygous for UGT1A1*28 allele
Lower UGT1A1 expression known as Gilberts
syndrome
Decreased SN-38 glucuronidation
Predictive factor for toxicities especially
neutropenia
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 DNA
replication
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


References
1. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Figure 5-25, The reversible nicking
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 Dysarthria. Case Rep Oncol.
2012 Jan-Apr; 5(1): 4751.
3. Briggs, Gerald G.; Freeman, Roger K.; Yaffe, Sumner J. Irinotecan. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk
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.micromedexsolutions.com/.
Accessed January 30, 2014.
8. Irinotecan (Rx) Camptosar, Dosing Forms and Strengths. Medscape. Available at http://reference.medscape.com/drug/camptosar-irinotecan-342252.
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 antihumor effect of CPT-
11. Cancer Res. 1991;51:4187-4191.
10. ODwyer P, Catalano R. Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arrives in Cancer
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 Biol.
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 Irinotecan-Induced
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 Adv Med Oncol.
2010 January; 2(1): 5163. doi: 10.1177/1758834009355164