1244

ABCC2

ATP-binding cassette, sub-family C (CFTR/MRP), member 2;ABCC2;ATP-binding cassette, sub-family C (CFTR/MRP), member 2

canalicular multidrug resistance protein|canalicular multispecific organic anion transporter 1|multidrug resistance-associated protein 2

10q24

protein-coding

ATP-binding cassette, sub-family C, number 2 (ABCC2) is involved in the biliary excretion of irinotecan and its metabolites, SN-38 and SN-38 glucuronide. Effects of the ABCC2 genotype on the pharmacokinetics (PK) of irinotecan and the metabolites were examined in Japanese patients with metastatic colorectal cancer receiving irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI). ABCC2 genotypes (-1549G>A, -1023G>A, -1019A>G, -24C>T, 1249G>A and 3972C>T) and haplotypes were analyzed for 67 patients with cancer. PK was also examined in a subset of 31 patients receiving FOLFIRI. Relationship between the ABCC2 genotypes or diplotypes and area under the time-concentration curve (AUC) of irinotecan and the metabolites normalized by irinotecan dose was analyzed. The lower AUC of irinotecan was seen in patients with A/A or G/A genotypes at 1249 of the ABCC2 gene than others (p=0.011, Mann-Whitney U teat). AUC of SN-38 in patients with A/A or G/A genotypes at -1023 was significantly lower than that in others (p=0.018). The haplotype I included -1023A (GAACGC) was the most frequent one with the allele frequency of 0.366. The AUC of SN-38 observed in patients with diplotypes harboring at least one haplotype I was lower than that observed in others (p=0.023). The haplotype IV consisted of 1249 (GGACAC) and was the fourth most frequent one with the allele frequency of 0.127. Patients with diplotypes carrying at least one haplotype IV showed lower AUC of irinotecan than others (p=0.011). Thus, ABCC2 genotype is one of the predictors of the variability of irinotecan PK in Japanese patients with metastatic colorectal cancer receiving FOLFIRI.

cancer metastasis and anti-cancer drug resistance are the major reason for the failure of clinical cancer treatment. We evaluated CD147, monocarboxylate transporters (MCT1 and MCT4), and multidrug resistance (MDR) markers (MDR1 and MRP2) in 4 epithelial ovarian cancer (EOC) cell lines and primary tumors (n = 120) along with the matched metastatic lesions (n = 40) with immunofluorescence labeling. We correlated CD147 with MCT1, MCT4, MDR1 and MRP2 markers in primary and metastatic cells in cell lines and tissues using confocal microscopy. We also investigated the relationship of expression of CD147, MCT1 and MCT4 with various progression parameters. Our results indicate that the co-expression of CD147 with MCTs or MDR markers was found in primary and metastatic EOC cells and stromal cells; the over-expression of CD147, MCT1 and MCT4 was found in most primary and the matched metastatic lesions of EOC, and was significantly associated with tumor stage, grade, residual disease status and presence of ascites (P < 0.05) but not with histology type (P > 0.05). These results suggest that over-expression of CD147, MCT1 and MCT4 is correlated with EOC progression, and co-expression of CD147 and MCT1/MCT4 is related to drug resistance during EOC metastasis and could be useful therapeutic targets to prevent the development of incurable, recurrent and drug resistance EOC.