Breast Cancer Resistance Protein

The role of BCRP (or ABCG2) seems to be to protect tissues by actively transporting toxic substances and xenobiotics out of the cells. Cancer cells overexpressing ABCG2 show multidrug resistance to mitoxantrone-, methotrexate-, doxorubicin-, and camptothecin-based anticancer drugs, such as topotecan and SN-38. Large interindividual differences have been observed in oral availability and clearance of drugs that are substrates for ABCG2, especially topotecan (73). Genetic variation in the ABCG2 gene could possibly explain the variability in pharmacokinetics of ABCG2 substrates. SNPs have already been reported in the ABCG2 gene (74-76).

Mizuarai et al. (77) analyzed the effect of the polymorphisms G34A and C8825A, leading to an amino acid change of V12M and Q141K, respectively, on the transporter function of the protein. Drug resistance to indolocarbazole, a topoi-somerase I inhibitor, of cells expressing V12M or Q141K was less than 1/10 compared to wild-type ABCG2-transfected cells and was accompanied by increased drug accumulation and decreased drug efflux in the variant ABCG2-expressing cells. A possible explanation for this altered function of the ABCG2 enzyme is the fact that the ABCG2 transporter is not localized to the apical membrane in the V12M clone. However, it is not known if the altered transport function of ABCG2 influences drug transport in vivo.

In a study by Imai et al. (78), Japanese volunteers with the mutant C8825A polymorphism (allele frequency of 46%) expressed a low amount of the Q141K ABCG2 protein. The pharmacokinetics of diflomotecan have been affected by this polymorphism (79). Patients heterozygous for this allele showed statistically significant increased plasma levels in comparison to patients with wild-type alleles. De Jong et al. (80), however, showed that no significant changes in irinotecan pharmacokinetics in vivo were observed in relation to the ABCG2 C8825A genotype, although one of two homozygous variant allele carriers showed extensive accumulation of SN-38 and SN-38G.

In AML cells, ABCG2 is overexpressed; however, the association between the expression and clinical resistance to anticancer drugs remains undetermined (81,82). The identification of functional sequence variation in the ABCG2 gene could also be of interest in the field of prognosis of disease.

In conclusion, to date no in vivo effects of BCRP polymorphisms have been detected in relation to efficacy and toxicity of anticancer drugs that are substrates for BCRP.

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