10.2217/146224184.108.40.2061 © 2008 Future Medicine Ltd ISSN 1462-2416Pharmacogenomics (2008) 9(6), 671–674
NEWS & VIEWS
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Pharmacogenomics of importance for
Clinical Pharmacology, Department of Medical &
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Paclitaxel (Taxol®) has a broad activity spectrum and is clinically used, often in
combination with carboplatin, to treat breast, ovarian and lung cancer. The
response to treatment and the severity of adverse drug reactions after
chemotherapy varies greatly among individuals, and one of the most important
factors responsible for these differences is now recognized to be the genetic
variability. However, so far only genetic variants of ABCB1 have been indicated
to be associated with response and pharmacokinetics of paclitaxel.
Commercially, the patent on paclitaxel has expired; however, from a
healthcare perspective, it would be beneficial to identify patients with risk of
poor response or high risk of toxicity to reduce hospitalization costs. This article
focuses on the pharmacogenomic background for paclitaxel response and
• Despite paclitaxel’s clinical activity, the
variability in toxicity, response and
pharmacokinetics are high and a
• It has been indicated that the genetic
polymorphism of CYP2C8, CYP3A4
and P-glycoprotein (ABCB1) could
affect the response and
pharmacokinetics of paclitaxel.
• The gene corresponding to the target
protein β-tubulin is highly conserved,
and genetic variability does not
correlate to response.
Predicting the response, toxicity and
pharmacokinetics during treatment with
paclitaxel would be highly desirable, in
the sense that it would be possible to
identify patients with a high risk of
adverse events, patients who would bene-
fit from the treatment and/or patients
who might need a higher dose to get a
better response. Like most drugs, the
effects of paclitaxel are dependent on sev-
eral proteins. Paclitaxel exerts its cyto-
toxic effect by binding to β-tubulin,
thereby stabilizing the microtubule and
inducing apoptosis . Systemic elimina-
tion of paclitaxel occurs by hepatic
metabolism involving the CYP enzymes,
CYP3A4 and CYP2C8. Paclitaxel is
also a substrate for P-glycoprotein,
encoded by the ABCB1 (MDR-1) gene,
which functions as a transporter and is
believed to be an important factor in the
resistance to [3,4] and biliary elimination
of  many drugs, including paclitaxel
(Figure1). One of the major obstacles to
successful treatment is drug resistance.
Several potential mechanisms have been
suggested for the resistance to paclitaxel,
such as mutations in the target protein
β-tubulin and SNPs in the ABCB1 gene.
Another reason might be the high inter-
individual variability of paclitaxel plasma
concentrations, which has been sug-
gested to be influenced by variability in
metabolic enzymes and transport
proteins, such as P-glycoprotein.
Mutations in β-tubulin have been
indicated as a potential resistance mech-
anism. However, recent studies have
shown that the β-tubulin gene M40
(main isotype) is highly conserved, and
that mutations in the gene are unlikely
to be a clinically relevant explanation of
resistance to paclitaxel [6–8].
Different polymorphisms in the
ABCB1 gene have been identified, and
of these SNPs, G1199T/A and the
linked G2677T/A (Ala893Ser/Thr)
and C3435T (Ile1145Ile, wobble) have
been associated with altered P-glycopro-
tein expression and phenotype[9–11].
G2677T/A were shown to be associated
with the progression-free survival after
paclitaxel treatment [12,13]. The ABCB1
SNP C3435T has also been associated
with paclitaxel-mediated peripheral neu-
ropathy and neutropenia . In another
study, the progression-free survival, but
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Pharmacogenomics (2008) 9(6)
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not the CA-125 or the clinical/radiolog-
ical response, was indicated to correlate
to the G2677T/A , although the
effects of docetaxel and paclitaxel were
not distinguished. However, none of this
was confirmed in a similar study .
The AUC of paclitaxel has also been cor-
related to the ABCB1 genotype, espe-
cially the number of variant alleles .
However, in other studies no correlation
has been found between the pharmacok-
inetics of paclitaxel and the ABCB1
genotype[14,18,19]. In the most compre-
hensive study so far, a high interindivid-
ual variation in the clearance of
unbound paclitaxel (tenfold) was found,
and no statistical significant association
was observed between any variant geno-
type and the pharmacokinetics of
paclitaxel . However, a wide range of
dosage and infusion times were used in
CYP2C8*3 has been associated with
an altered turnover of paclitaxel invitro
[21–23]. So far, CYP2C8*3 has not been
associated with either altered pharmaco-
kinetics of paclitaxel in vivo, or
response to paclitaxel treatment .
The large interindividual variation in
CYP3A4 activity is more difficult to
explain on a genetic basis , although
CYP3A4*1B seems to affect enzyme
activity . For paclitaxel, genetic varia-
tions in CYP3A4 might be associated
with an altered pathway of paclitaxel
metabolism , but probably not the
total clearance of the drug.
Several other genes have been sug-
gested to affect the response to and
pharmacokinetics of paclitaxel. In a breast
cancer study, CYP1B1*3 was associated
with paclitaxel outcome , but this was
not reproduced in a study of ovarian
cancer . SLCO1B3 (OATP1B3 gene)
has been shown to transport paclitaxel
into the hepatocytes (Figure1), but no
association has been found between the
pharmacokinetics of paclitaxel and SNPs
in the gene . ABCG2 and ABCC2
genetic variants have also been suggested
to play a role in paclitaxel treatment, but
no correlations to paclitaxel efficacy has
been found .
In conclusion, there is an indication
that genetic variations in ABCB1 might
be associated with response to paclitaxel
Figure 1. Elimination of paclitaxel from the circulation via the hepatocyte to the bile.
Elimination of paclitaxel from the circulation is believed to be dependent on several polymorphic proteins. The transport into the
hepatocyte is believed to be mediated by SLCO1B3 (encoded by the OATP1B3 gene). Paclitaxel can then be converted to
p-3´ -hydroxypaclitaxel (p-3-OH-pac) by CYP3A4, and CYP2C8 catalyzes the formation of 6α-hydroxypaclitaxel (6α-OH-pac). These
metabolites can be further oxidized to 6α-, p-3´ -dihydroxypaclitaxel (di-OH-pac) by the same enzymes. Both unchanged paclitaxel and the
metabolites are then excreted from the hepatocyte by P-glycoprotein (encoded by the ABCB1 gene).
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treatment and altered pharmacokinetics.
However, the literature is not conclusive
on this matter. To date, no other genetic
variant has been conclusively shown to
have an affect on paclitaxel treatment.
An excellent review on paclitaxel phar-
macogenetics has been written by
S Marsh, which I would recommend .
The largest studies so far on the
pharmacogenetics of paclitaxel have been
carried out by Henningsson etal.  and
Marsh etal. , where Hennigsson did
not find any association to altered phar-
macokinetics of paclitaxel, and Marsh
did not find any correlation to the
response. However, both these studies
do have some issues that might have
affected the results.
CA-125 is an indicator for an irritated
abdominal cavity, both from cancerous
and benign causes. It can be used as a
marker for ovarian cancer and for mon-
itoring tumor response during treat-
ment with, for example, paclitaxel. At
present, there are no diagnostics or
markers that have been validated for
prediction of paclitaxel adverse drug
reactions. However, I would anticipate
that in the future, SNP methodology,
such as pyrosequencing, will be used for
identifying individuals at high risk for
adverse drug reactions and as a tool for
Financial & competing interests
The author has no relevant affiliations or
financial involvement with any organization or
entity with a financial interest in or financial
conflict with the subject matter or materials
discussed in the manuscript. This includes
employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or
patents received or pending, or royalties.
No writing assistance was utilized in the
production of this manuscript.
1. Rowinsky EK, Cazenave LA,
DonehowerRC: Taxol: a novel
investigational antimicrotubule agent. J.Natl
Cance r Ins t. 82(15), 1247–1259 (1990).
2. Walle T, Walle UK, Kumar GN,
BhallaKN: Taxol metabolism and
disposition in cancer patients. Drug Metab.
Dispos. 23(4), 506–512 (1995).
3. Kamazawa S, Kigawa J, Kanamori Y et al.:
Multidrug resistance gene-1 is a useful
predictor of paclitaxel-based chemotherapy
for patients with ovarian cancer. Gynecol.
Oncol. 86(2), 171–176 (2002).
4.Penson RT, Oliva E, Skates SJ, Glyptis T,
Fuller AF Jr, Goodman A, Seiden MV:
Expression of multidrug resistance-1
protein inversely correlates with paclitaxel
response and survival in ovarian cancer
patients: a study in serial samples. Gynecol.
Oncol. 93(1), 98–106 (2004).
5. Sparreboom A, van Asperen J, Mayer U
etal.: Limited oral bioavailability and
active epithelial excretion of paclitaxel
(Taxol®) caused by P-glycoprotein in the
intestine. Proc. Natl Acad. Sci. USA 94(5),
6. Sale S, Sung R, Shen P et al.: Conservation
of the Class I β-tubulin gene in human
populations and lack of mutations in lung
cancers and paclitaxel-resistant ovarian
cancers. Mol. Cancer Ther. 1(3), 215–225
Green H, Rosenberg P , Soderkvist P ,
Horvath G, Peterson C: β-tubulin
mutations in ovarian cancer using single
strand conformation analysis-risk of false
positive results from paraffin embedded
tissues. Cancer Lett. 236(1), 148–154
Kelley MJ, Li S, Harpole DH: Genetic
analysis of the β-tubulin gene, TUBB, in
non-small-cell lung cancer. J. Natl Cancer
Inst. 93(24), 1886–1888 (2001).
Hoffmeyer S, Burk O, von Richter O
et al.: Functional polymorphisms of the
human multidrug-resistance gene:
multiple sequence variations and
correlation of one allele with
P-glycoprotein expression and activity
invivo. Proc. Natl Acad. Sci. USA 97(7),
10. Tanabe M, Ieiri I, Nagata N et al.:
Expression of P-glycoprotein in human
placenta: relation to genetic polymorphism
of the multidrug resistance (MDR)-1 gene.
J. Pharmacol. Exp. Ther. 297(3),
11. Kim RB, Leake BF, Choo EF et al.:
Identification of functionally variant
MDR1 alleles among European Americans
and African–Americans. Clin. Pharmacol.
Ther. 70(2), 189–199 (2001).
12. Green H, Soderkvist P , Rosenberg P ,
Horvath G, Peterson C: mdr-1 single
nucleotide polymorphisms in ovarian
cancer tissue: G2677T/A correlates with
response to paclitaxel chemotherapy. Clin.
Cancer Res. 12(3 Pt 1), 854–859 (2006).
13. Green H, Soderkvist P , Rosenberg P ,
Horvath G, Peterson C: ABCB1 G1199A
polymorphism and ovarian cancer
response to paclitaxel. J. Pharm. Sci. 97(6),
14. Sissung TM, Mross K, Steinberg SM et al.:
Association of ABCB1 genotypes with
paclitaxel-mediated peripheral neuropathy
and neutropenia. Eur. J. Cancer 42(17),
15. Marsh S, Paul J, King CR, Gifford G,
McLeod HL, Brown R: Pharmacogenetic
assessment of toxicity and outcome after
platinum plus taxane chemotherapy in
NEWS & VIEWS – Drug Focus: paclitaxel
Pharmacogenomics (2008) 9(6)
future science group future science group
ovarian cancer: the Scottish Randomised
Trial in Ovarian Cancer. J. Clin. Oncol.
25(29), 4528–4535 (2007).
16. Ludwig AH, Kupryjanczyk J: Does
MDR-1 G2677T/A polymorphism really
associate with ovarian cancer response to
paclitaxel chemotherapy? Clin. Cancer Res.
12(20), 6204 (2006).
17. Yamaguchi H, Hishinuma T, Endo N
etal.: Genetic variation in ABCB1
influences paclitaxel pharmacokinetics in
Japanese patients with ovarian cancer.
Int. J. Gynecol. Cancer 16(3), 979–985
18. Nakajima M, Fujiki Y, Kyo S et al.:
Pharmacokinetics of paclitaxel in ovarian
cancer patients and genetic
polymorphisms of CYP2C8, CYP3A4, and
MDR1. J. Clin. Pharmacol. 45(6),
19. Henningsson A, Marsh S, Loos WJ et al.:
Association of CYP2C8, CYP3A4,
CYP3A5, and ABCB1 polymorphisms
with the pharmacokinetics of paclitaxel.
Clin. Cancer Res. 11(22), 8097–8104
20. Soyama A, Saito Y, Hanioka N et al.:
Non-synonymous single nucleotide
alterations found in the CYP2C8 gene
result in reduced in vitro paclitaxel
metabolism. Biol. Pharm. Bull. 24(12),
21. Dai D, Zeldin DC, Blaisdell JA et al.:
Polymorphisms in human CYP2C8
decrease metabolism of the anticancer
drug paclitaxel and arachidonic acid.
Pharmacogenetics 11(7), 597–607 (2001).
22. Bahadur N, Leathart JB, Mutch E et al.:
CYP2C8 polymorphisms in Caucasians
and their relationship with paclitaxel
6alpha-hydroxylase activity in human liver
microsomes. Biochem. Pharmacol. 64(11),
23. Lamba JK, Lin YS, Schuetz EG,
Thummel KE: Genetic contribution to
variable human CYP3A-mediated
metabolism. Adv. Drug Deliv. Rev. 54(10),
24. Rodriguez-Antona C, Sayi JG,
GustafssonLL, Bertilsson L,
Phenotype–genotype variability in the
human CYP3A locus as assessed by the
probe drug quinine and analyses of variant
CYP3A4 alleles. Biochem. Biophys. Res.
Commun. 338(1), 299–305 (2005).
25. Nakajima Y, Yoshitani T, Fukushima-
Uesaka H et al.: Impact of the haplotype
CYP3A4*16B harboring the Thr185Ser
substitution on paclitaxel metabolism in
Japanese patients with cancer. Clin.
Pharmacol. Ther. 80(2), 179–191 (2006).
26. Marsh S, Somlo G, Li X et al.:
Pharmacogenetic analysis of paclitaxel
transport and metabolism genes in breast
cancer. Pharmacogenomics J. 7(5), 362–365
27. Smith NF, Marsh S, Scott-Horton TJ
etal.: Variants in the SLCO1B3 gene:
interethnic distribution and association
with paclitaxel pharmacokinetics. Clin.
Pharmacol. Ther. 81(1), 76–82 (2007).
28. Marsh S: Taxane pharmacogenetics.
Personalized Medicine 3(1), 33–43 (2006).