| |
Taxanes, such as paclitaxel and docetaxel, are widely prescribed chemotherapeutic drugs
[PMID: 15057285, 15161985, 18068131]. They have been used to treat many forms of cancer including
breast, ovarian and lung cancers [PMID:15057285]. Paclitaxel was isolated from the Pacific yew in
1971 and docetaxel, a second generation taxane, is a semi-synthetic taxane analogue from the European
yew identified approximately 20 years later [PMID:15161985]. The pathway above depicts the known
candidate pharmacogenes involved in the pharmacokinetics and pharmacodynamics of taxanes.
Microtubules display a form of non-equilibrium dynamics referred to as dynamic instability that
is essential to cell division [PMID:18068131]. Dynamic instability is regulated by microtubule-
associated proteins (MAPs) including MAPT, MAP2 and MAP4 [PMID:18068131]. In an un-phosphorylated
state, the MAP proteins bind and stabilize microtubules, leading to cell death [PMID:18068131].
Microtubules are composed of α-tubulin and β-tubulin heterodimers [PMID:15057285]. Taxanes
block cell division by binding to β-tubulin, stabilizing the microtubules, leading to cell death
[PMID:7627725, 15057285]. A 3.5A structure of bovine αβtubulin, with bound paclitaxel, can be
found in the Protein Data Bank [PMID: 10592235], entry 1JFF [PMID:11700061]. In addition, in
vitro studies have shown taxanes to induce BCL2 phosphorylation and apoptosis, with docetaxel
doing so at much lower concentrations than paclitaxel [PMID:9000560, 7753834].
While paclitaxel and docetaxel share many common structural features, their pharmacology and
pharmacokinetics differ somewhat. Consequently, in some patients, solid tumors with resistance
to paclitaxel have been shown to be sensitive to docetaxel [PMID:9779713, 10894873].
The pharmacokinetics of taxanes are complex and are complicated by their different formulations
[11392447]. Both taxanes are primarily metabolized in the liver and their primary route of
elimination of the parent drug and hydroxylated metabolite is through biliary excretion via feces
[PMID:15161985]. Early work found that docetaxel had linear pharmacokinetics but paclitaxel did not
[PMID:15161985, 7799018] . However, the two taxanes have different formulations: paclitaxel is
dissolved in Cremophor EL (CrEL, poly-oxyethyleneglycol triricinoleate 35)/ethanol (1:1) where as
docetaxel is dissolved in polysorbate 80 (Tween 80) [12844327]. Tween 80 was found to alter the
fraction of unbound docetaxel in patients [12844327] and another study found that in the absence
of CrEL the bioavailability of intraperitoneal paclitaxel was significantly increased [11948138].
Various other studies have shown that CrEL alters the pharmacokinetic behavior of many drugs,
including paclitaxel [12844327, 11527683]. Finally, a small study of the recently available,
130-nm albumin-bound (nab) particle formulation of paclitaxel,, devoid of solvents, found that
the disposition of paclitaxel is subject to considerable variability, depending upon the
formulation used [18594000].
Both paclitaxel [PMID: 9492385, 7473140] and docetaxel [PMID: 9492385,15116057, 10092957, 9825831]
are metabolized by CYP3A4. Paclitaxel is also metabolized by CYP2C8 [PMID:11668219, 11901098], while
docetaxel is also metabolized by CYP3A5 [PMID:9825831]. In an in vitro study, a highly significant
induction level of PXR (gene NR1I2) -mediated CYP3A4 expression was observed for paclitaxel, whereas
docetaxel only moderately increased CYP3A4 expression [PMID: 18839173]. In another study, paclitaxel
activated PXR, but docetaxel did not [11329060]. Paclitaxel was also found to activate PXR and
enhances P-glycoprotein (ABCB1) mediated drug clearance [11329060] and ABCB1 expression [15650019]
as well as CYP2C8 expression [15933212].
Both paclitaxel and docetaxel are substrates for the ATP binding cassette multidrug transporters
ABCB1, ABCG2, ABCC1 and ABCC2 [PMID:12608532, 11059771, 9610729, 12417570, 14617793, 17062689, 15849751].
OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel [PMID:18509327] and
identified as a key regulator of paclitaxel hepatic uptake [16210916, 17186002]. OAT2 (SLC22A7) was found
to transport paclitaxel in in vitro experiments [15901346].
Taxane resistance is frequent [PMID:17216190, 18068131, 15720262]. Possible mechanisms for such
resistance are many, but definitive data for the causes of resistance remain unclear. There are
several genes that encode α- and β-tubulins and different tubulins also arise from different
post-translational modifications [PMID:9348671]. Such structural diversity makes comparative
analysis between tubulins in drug-sensitive and drug-resistant cell lines difficult [PMID:14556633].
Exposure to taxane creates somatic mutations in tubulins, but the relationship of somatic mutations
to resistance remains unclear, even for those mutations near the taxane binding site [PMID:19455242].
While an early study found a relationship between mutations in the tubulin-encoding TUBB gene and
paclitaxel treatment response and clinical outcome (in tissue samples of patients with advanced
non-small-cell lung cancer) [10561216], numerous other genetic and mutational analysis of the gene
in cell lines and patients with lung cancer, breast cancer and ovarian cancer did not find such a
relationship [11752014, 11750707, 12011233, 12209967, 12893435, 16095531,16002208, 12209587,
12826311, 12680167], suggesting that mutations in TUBB do not play a role in taxane resistance.
Genetic and mutational analysis of the TUBB gene has been complicated due to the presence of
several pseudogenes with high homology to the wild type gene [12826311, 12209587]. Increased
expression level of tubulins as a mechanism for resistance remains contradictory, although there
growing evidence that this does lead to resistance for particular tubulins [PMID:19455242].
Recently, high levels of chromosomal instability, and the genes involved in this instability,
have been found to be related to taxane resistance [PMID:19458043]
Pharmacogenetics:
The impact of genetic variants on taxane response is unclear: several studies did not find relationships
between polymorphisms of genes in the taxane pathway, while others did. For example, in a large study
(n=914) of ovarian cancer patients from the Scottish Randomized Trial in Ovarian Cancer (SCOTROC) phase
III trial who were treated at presentation with carboplatin and taxane regimens, no association between
polymorphisms of genes in the pathway and taxane response was found [PMID:17925548]. This study assessed
polymorphisms in 11 genes (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, and
TP53) and found no reproducible significant associations between genotype and outcome or toxicity
[PMID:17925548]. Similarly, in two other studies, no significant association was seen between ABCB1,
ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance or ABCB1, CYP2C8, CYP3A4 and
CYP3A5 and paclitaxel clearance [PMID:17224914, 16299241].
In contrast, other studies of genes in the taxane pathway did find associations between polymorphisms
of the genes and either patient survival or drug response. With respect to survival, one study found
rs1056836, CYP1B1*3 (4326 C>G; L432V) allele, was significantly associated with progression-free survival,
independent of paclitaxel clearance [PMID:17224914]. The same SNP was also associated with survival in
patients receiving docetaxel [PMID: 18187806]. In a recent study of patients with metastatic breast cancer,
the synonymous variant rs1045642 (ABCB1: 3435 C>T), showed a significantly lower disease control rate and
lower overall survival rate than the CC genotype for the variant allele [PMID:18836089].
Other small studies have found associations between variants of ABCB1 and taxane pharmacokinetics..
One small study of Japanese patients found associations with ABCB1 polymorphisms, including paclitaxel
pharmacokinetics and ABCB1 variants [PMID:16803472]. Another small study of Japanese patients found that
those with the ABCB1:3435C>T (rs1045642) allele had a significantly higher AUC of a paclitaxel
metabolite when compared to those possessing the 3435C allele[15901749]. Other studies associated
ABCB1: 2677G>T/A with response to paclitaxel [PMID: 16467099] , response to taxane- and platinum-based
chemotherapy [PMID: 19203783] and gastrointestinal toxicity [PMID: 19203783]. A combination of
ABCB1:2677G>T/A and ABCB1:3435C>T (rs1045642) genotypes have been associated with neutropenia
from paclitaxel therapy [PMID: 16950614]. A recent small study of Caucasian patients found
that the interindividual variability in paclitaxel clearance to be related to variants in ABCB1;
in particular, patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher
clearance of paclitaxel than most other ABCB1 variants [19143748].
That same study found variability in paclitaxel clearance to also be related to CYP2C8 genotype;
the CYP2C8*3 had lower clearance of paclitaxel [19143748].. Another recent small study of docetaxel
clearance found greater clearance with patients with the CYP3A4*1B and CYP3A5*1A alleles [PMID:18509327].
Most of these findings remain to be validated.
|
