Irinotecan the potential to substantially regulate irinotecan

Irinotecan

Camptothecin analogs were developed in the 1990s to
prevent the solubility problems associated with camptothecin, a cytotoxic agent
developed as an anticancer agent in the early 1970s. Camptothecin and its
analogs inhibit DNA topoisomerase I eventually preventing DNA re-ligation
leading to the failure of the replication machinery 1. Irinotecan (also known
as CPT-11) is one of the analogs approved for first-line therapy of advanced
colorectal cancer in combination with 5-fluorouracil and/or leucovorin. In addition,
irinotecan has also been used with cisplatin as a combination therapy for other
cancers, such as lung and ovarian 2.

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The major limiting factors of irinotecan are diarrhea
and neutropenia that can range from severe to potentially life-threatening. The
gastrointestinal and vascular effects have been associated with a high
mortality rate in patients receiving the combination of irinotecan with bolus
fluorouracil and leucovorin during the first 60 days of therapy. The severity
of toxicities and effectiveness of irinotecan therapy vary greatly in
populations due to genetic differences in different factors involved in
pharmacokinetics and pharmacodynamics. Pharmacogenomics can be applied to
screen patients for such genetic (DNA variations) prior to selecting irinotecan
therapy so as to optimize its therapy and reduce health care costs 3.

Irinotecan pharmacokinetics

Irinotecan is a prodrug which is converted to SN-38 by
carboxylesterase 2, resulting in a greater than 1,000-fold enhancement of
cytotoxic activity. Irinotecan, before activation, is processed by cytochrome
P450 (CYP450) enzymes and transported by ATP-Binding Cassette (ABC) efflux
pumps. The active metabolite either binds to topoisomerase-I of the target
(tumor) cell or is exported out of the cell via efflux pumps. SN-38 can also be
inactivated by glucuronide conjugation.  While
each of these steps has the potential to substantially regulate irinotecan
activity, it is glucuronidation by the protein UGT1A1 that has the clearest
potential impact on patient care.

Uridine-diphosphate glucoronosyl transferase (UGTs)
are responsible for glucoronidation of lipophilic compounds that converts them
to more polar form. UDP-glucoronic acid is used as a co-substrate for the
reaction that catalyzes a variety of substrates such as bilirubin, hormones,
drugs, and other xenobiotics, leading to the formation of more hydrophilic
conjugates facilitating their elimination through bile and urine.

Metabolism

Irinotecan is a prodrug, metabolized into the active
form, SN-38, via human carboxylesterases CES1 and CES2, primarily in the liver.
Irinotecan is converted into APC, an inactive metabolite by CYP3A4. The active
SN-38 can be subsequently inactivated through glucoronidation via members of
the UDP glucuronosyltransferase (UGT) family. A total of 13 UGT1A genes are
encoded at the UGT1A locus located on chromosome 2q37t. Each UGT1A enzyme has a
unique promoter and a unique exon 1, while the remaining four exons are shared
with all members of the UGT1A family 4.

Metabolism pharmacogenomics

CES2—CPT-11 is
hydrolyzed to the active form, SN-38, primarily by carboxylesterase-2 (CES2).
CES2 expression is highly variable among individuals, and increased CES2
expression leads to increased irinotecan metabolism 5. However, researchers
have not been able to identify any functional polymorphisms associated with the
CES2 gene expression. Some of the minor individual variations in CES2 expression
can be attributed to the control of its three distinct promoters 6. CES1
plays a minor role in irinotecan metabolism.

CYP3A4—CYP3A4
inactivates irinotecan through conversion into the metabolite APC. While there
is no evidence of variants in the CYP3A4 gene providing a useful screen for APC
conversion, the interindividual variability in CYP3A4 activity can be exploited
for irinotecan dosing 7.

UGT1A1—The most
comprehensively studied genetic marker linked to toxicity from irinotecan
therapy is found in the UDP-glucuronosyltransferase gene, UGT1A1. The UGT1A1
enzyme is responsible for hepatic bilirubin glucuronidation, and reduced UGT1A1
expression leads to Gilbert’s syndrome, a condition characterized by rise in
the plasma levels of unconjugated bilirubin. In fact, three forms of heritable
unconjugated hyperbilirubinemias exist in humans including Crigler-Najjar
syndrome type 1 and type 2 and Gilbert’s syndrome. These heritable syndromes
are all the result of low activity UGT1A1 gene or promoter alleles. A
polymorphic dinucleotide repeat within the UGT1A1 promoter TATA element consisting
of between five and eight copies of a TA repeat (TAnTAA) control the
expression of UGT1A1 gene. The (TA)6TAA allele is the most common (considered
wild-type) and (TA)7TAA is the most frequently recorded variant allele (usually
denoted UGT1A1*28) 8. The length of the repeat allele has been found to be
inversely proportional to UGT1A1 expression, that is, the longer the repeat
allele, the lower the corresponding UGT1A1 gene expression. The frequency of
the UGT1A1*28 allele has been assessed worldwide and ranges from approximately
15% in Asians to 45% in Africans. It is also found in 26–38% of Caucasians,
African–Americans and Hispanics. The decrease in expression of UGT1A1 gene
leads to reduced glucoronidation leading to build up of SN-38 metabolite in the
plasma, leading to increased toxicity 8.

 Many studies have
established the link between UGT1A1*28 and irinotecan toxicity, and a prospective
study of 66 patients with advanced disease treated with irinotecan found that patients
homozygous for UGT1A1*28 had a significantly greater risk of grade IV neutropenia
compared with patients with at least one wild-type allele.

Other UGT1A1 polymorphisms—There
are other significant polymorphisms in the UGT1A1 gene. Patients with
haplotypes containing both the ?3156G>A variant and UGT1A1*28 experienced
significantly higher incidence of severe neutropenia compared with patients
with haplotypes not containing ?3156G>A 9.

In Asian populations where the frequency of UGT1A1*28
is low, other UGT1A1 variants can also play a role in irinotecan toxicity. For
example, in Korean patients with non-small-cell lung cancer treated with
irinotecan-containing therapy, there were associations between, irinotecan pharmacokinetics,
and toxicity from irinotecan therapy.

Other UGT1A genes—Variants
in UGT1A7 and UGT1A9 are also associated with SN-38 glucuronidation and
irinotecan toxicities, although these studies require further exploration. UGT1A7*3
has been associated with hematologic toxicity in metastatic colorectal cancer
patients treated with irinotecan 10. Furthermore, UGT1A7*2 and *3, as well as
UGT1A9 -118(dT) alleles, were associated with response to irinotecan.

 

 

Transport

Irinotecan and SN-38 may be transported out of the cell
via members of the ATP-binding cassette transporter family 11, specifically
ABCB1 (MDR1; P-glycoprotein), ABCC2 (CMOAT; MRP2) and ABCG2 (BCRP). In
addition, glucuronidated SN-38 can be removed from the cell by ABCC2.

Transport pharmacogenomics

ABCB1—ABCB1 1236C>T
variants and ABCB1 3435C>T have been associated with decreased clearance of
irinotecan and irinotecan-induced diarrhea respectively in two independent
studies 56,57. In a further study, a haplotype containing the three most
commonly studied ABCB1 polymorphisms (1236C>T, 2677G>T and 3435C>T)
was associated with reduced renal clearance in 49 Asian patients receiving
irinotecan 11.

ABCC2—In 64 patients
with solid tumors treated with irinotecan, a significant correlation was
observed with irinotecan and metabolite clearance, and the 3972T>C
polymorphism, which was also associated with toxicity. ABCC2 -24T homozygotes
and 3972T homozygotes also experienced significantly better response rates and
progression-free survival in non-small-cell lung cancer patients receiving
irinotecan and cisplatin. In addition, a haplotype in the multidrug transporter
ABCC2 is associated with toxicity in patients lacking UGT1A1*28, suggesting
that this haplotype could be a secondary screen for patients who are wild-type
for UGT1A1, to further reduce the risk of toxicity 12.

ABCG2—Cell lines
overexpressing ABCG2 are resistant to several topoisomerase I inhibitors,
including irinotecan and SN-38. The ABCG2 variant 421C>A (Q141K) reduced
ABCG2 gene expression and caused irinotecan resistance in cancer cell lines and
neutropenia in 55 patients receiving irinotecan monotherapy when assessed as a haplotype
with ABCG2 IVS12 +49G>T 13. Alone, the ABCG2 421C>A variant was not associated
with toxicity. A further polymorphism, ABCG2 34G>A, was significantly associated
with diarrhea in 107 cancer patients but was not associated with toxicity or outcome
in 107 non-small-cell lung cancer patients.

Irinotecan pharmacodynamics

Topoisomerase-I is the target for SN-38, and several
downstream genes have been associated with camptothecin sensitivity, and are
consequently included in the irinotecan pathway including XRCC1, ADPRT, TDP1,
CDC45L and NF- ?B1.

Future perspective

Toxicity is a major dose-limiting, life-threatening
side effect from irinotecan chemotherapy. UGT1A1*28 has been shown to be one of
the prominent genetic markers that can be used to screen patients prior to
irinotecan therapy and/or individualize dosage regimen that would improve its
therapy and prove to be a cost-effective approach. However, the difficulty of
interpreting genetic information to the benefit of a patient and the fact that,
UGT1A1*28 polymorphism does not account for all the variability in the
irinotecan therapy still present the problems with the clinical application of
pharmacogenomic approaches. Hence, screening for the allele does give promising
inputs to the clinician about the patients at risk, but, that does not preclude
the chances of a patient experiencing severe toxicity.

Alongside variants in other UGT1A genes, transporters,
and pharmacodynamic genes, in vitro studies have shown that altered expression
of PXR can affect SN-38 glucuronidation. Consequently, variation in the expression
of PXR should be explored in the context of irinotecan therapy. Recent work has
also suggested that epigenetic factors, such as DNA and histone methylation,
may also play a role in altering UGT1A1 expression 14, and it is possible
that screening of the tumor cells as well as germline DNA may also be needed for
a comprehensive irinotecan pharmacogenomic profile.

Conclusion

Variation in any gene involved in the irinotecan
pathway could play a role in either toxicity or response, although, UGT1A1*28
provides can be a strong target to screen for irinotecan toxicity. A
comprehensive pharmacogenomic profile associated with irinotecan is needed
which includes polymorphisms or other genomic alterations such as epigenetic.
Currently, markers for irinotecan response are few, and many remain
unvalidated. Further analysis, of pharmacogenomics of irinotecan, will hopefully
identify the genetic basis of response to irinotecan.

 

References

1. Rothenberg ML. The current status of irinotecan
(CPT-11) in the United States. Ann. NY Acad. Sci 1996; 803:272–281

2. Devore R 3rd, Johnson D, Crawford J, Dimery I,
Eckardt J, Eckhardt SG. Irinotecan plus cisplatin in patients with advanced
non-small-cell lung cancer. Oncology (Williston Park) 1998;12(8 Suppl. 6): 79–83.

3. Marsh S, McLeod HL. Cancer pharmacogenetics.
Br. J. Cancer 2004;90(1):8–11.

4. Gong QH, Cho JW, Huang T, et al. Thirteen UDP
glucuronosyltransferase genes are encoded at the human UGT1 gene complex locus.
Pharmacogenetics 2001;11(4):357–368.

 

5. Yano H, Kayukawa S, Iida S, et al. Overexpression
of carboxylesterase-2 results in enhanced efficacy of topoisomerase I
inhibitor, irinotecan (CPT-11), for multiple myeloma. Cancer Sci 2008;99(11):2309–2314

6. Wu MH, Chen P, Remo BF, Cook EH Jr, Das S, Dolan
ME. Characterization of multiple promoters in the human carboxylesterase 2
gene. Pharmacogenetics 2003;13(7):425–435.

7. van der Bol JM, Mathijssen RH, Creemers GJ, et al. A
CYP3A4 phenotype-based dosing algorithm for individualized treatment of
irinotecan. Clin. Cancer Res 2010;16(2):736–742.

8. Ando Y, Saka H, Ando M, et al. Polymorphisms of
UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic
analysis. Cancer Res 2000;60(24):6921–6926.

9. Innocenti F, Undevia SD, Iyer L, et al. Genetic
variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe
neutropenia of irinotecan. J. Clin. Oncol 2004;22(8):1382–1388.

10. Cecchin E, Innocenti F, D’Andrea M, et al. Predictive
role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on
the outcome of metastatic colorectal cancer patients treated with fluorouracil,
leucovorin, and irinotecan. J. Clin. Oncol 2009;27(15):2457–2465.

11. Sparreboom A, Danesi R, Ando Y, Chan J, Figg WD. Pharmacogenomics
of ABC transporters and its role in cancer chemotherapy. Drug Resist.
Update 2003;6(2):71–84.

12.  Innocenti
F, Kroetz DL, Schuetz E, et al. Comprehensive pharmacogenetic analysis of
irinotecan neutropenia and pharmacokinetics. J. Clin. Oncol
2009;27(16):2604–2614

13. Sai K, Saito Y, Maekawa K, et al. Additive
effects of drug transporter genetic polymorphisms on irinotecan
pharmacokinetics/pharmacodynamics in Japanese cancer patients. Cancer
Chemother. Pharmacol 2009;66(1):95–105.

14. Belanger AS, Tojcic J, Harvey M, Guillemette C. Regulation
of UGT1A1 and HNF1 transcription factor gene expression by DNA methylation in
colon cancer cells. BMC Mol. Biol 2010;11:9.

15. Irinotecan pathway, pharmacokinetics. https://www.pharmgkb.org/pathway/PA2001

 

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