Info

mRNA UGT1A1

Alleles

Polymorphism

Exons

UGT activity

UGT1A1*1

Normal

Normal

UGT1A1*6

211G>A

1

Reduced

UGT1A1*7

1456T>G

1

Reduced

UGT1A1*27

686C>A

5

Reduced

UGT1A1*28

(TA)7TAA

Promoter

Reduced expression

UGT1A1*29

1099C>G

4

Reduced

Figure 12 UGT1A1 gene structure and a partial list of genetic variants affecting promoter sequences and gene expression (UGT1A1*28) and coding sequences (UGT1A1*6, UGT1A1*7, UGT1A1*27, and UGT1A1*29), thus resulting in reduced UGT activity.

Figure 12 UGT1A1 gene structure and a partial list of genetic variants affecting promoter sequences and gene expression (UGT1A1*28) and coding sequences (UGT1A1*6, UGT1A1*7, UGT1A1*27, and UGT1A1*29), thus resulting in reduced UGT activity.

G1-like state. Disruption of microtubules also results in the induction of TP53 and inhibition of cyclin-dependent kinases. As a consequence, cells are arrested in the G2-M phase of the cell cycle, after which they may either undergo cell death by apoptosis or overcome the G2-M stop and continue in the division cycle depending on the tumor cell type. However, the mechanisms by which taxanes induce caspase activation and apoptosis are not yet defined. A possibility is that taxanes are able to induce the phosphorylation of bc1-xl/bc1-2 members and thereby inactivate their antiapoptotic activity and also upregulate p53 and p21/WAF-1 (49).

A major mechanism of resistance to taxanes involves the overexpression or mutation of specific tubulin isotypes. Upregulation of the B-III isotype is an important marker of resistance (50), and high concentrations of «-tubulin are associated with a decrease in paclitaxel sensitivity in MCF-7 breast cancer cells (51). More recently, the overexpression of HER2/neu oncoprotein in NIH3T3 cells was shown to be associated with a threefold increase in the expression of the B-IVa isotype in comparison with the parental line, leading to paclitaxel resistance in transformed cells (52).

Tubulin mutations are important determinants of paclitaxel sensitivity. The amino acid residues 1-31 and 217-233 have a relevant role in paclitaxel binding to the protein and mutations near these sites, such as Thr274Ile and Arg282Gln, may be associated with a drug-resistant phenotype (53). Therefore, mutational and gene expression analysis of tubulin isotypes might be of critical importance in assessing the degree of sensitivity of cancer cells towards taxanes.

Metabolism of paclitaxel in tissues is primarily dependent on inactivating biotransformation through hydroxylation at the C6' or C3' position of the C-13 side chain by cytochrome P450 (CYP) 2C8 and 3A4 isoforms, respectively. Several polymorphisms have been described in the encoding genes, such as CYP2C8*2, CYP2C8*3, CYP3A4*17, and CYP3A4* 18 (54,55), thereby providing a partial explanation for interpatient variability in drug pharmacokinetics (56,57).

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The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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