혈액암 환자의 항암제 내성유전자 mRNA 발현양상과 임상상에 관한 연구

Abstract

(Background) Although cytotoxic chemotherapy is the most effective treatment modality for patients with hematologic malignancy, one of the major problems related to chemotherapy is resistance to anticancer drugs. It is well known that multidrug resistance could be due in part to a higher incidence of drug resistance gene expression in cancer cells. Several molecular biological mechanisms have been identified as being associated with multidrug resistance genes. P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) are well-known transporters among the ATP-binding cassette (ABC) superfamily that pump out antitumor agents via an ATP-dependent process. In addition, there are many other transporters including cooper transporters, nucleoside transporters and non-ABC transporters. So far, there have been a few reports about relation between their expression profiles and clinical significance in hematologic malignancy patients.

(Methods) All specimens were obtained by bone marrow aspiration from 44 patients that are composed of 31 acute myeloid leukemia and 13 myelodysplastic syndrome and from 23 non hematologic malignant patients. Using the multiplex RT-PCR assay kit (DrugsporterⓇ), all samples were analyzed for 24 drug resistance genes, including 17 ABC transporters, two non-ABC transporter (LRP and ATP7B), 5 solute carrier (SLC) transporters, and one housekeeping gene (GAPDH). Relationship between expression levels of 24 resistance genes and clinical data such as response of chemotherapy and prognosis was statistically analyzed.

(Results) Transcripts of eight genes (ABCB4, ABCC6, ABCC9, ABCC11, ABCG2, ATP7B, SLC29A1 and SLC29A2) were not expressed in all bone marrow specimen. The mRNA expression of five genes (ABCA2, ABCC1, ABCC4, ABCC10 and MVP) in myeloid malignant subjects were statistically different than that of non-malignant subjects. Among 31 acute myeloid leukemia patients treated with cytarabine +/- anthracycline, 17 patients (54.8%) showed remission. The mRNA expression of 3 genes (ABCC1, ABCC4 and MVP) were statistically different between remission group and remission failure group in chemotherapy. Expression of 2 genes (ABCB5 and ABCC5) in acute myeloid leukemia patients was statistically significant In terms of prognosis. (Conclusion) These results suggest that mRNA expression of ABCC1, ABCC4 and MVP in acute myeloid leukemia patients could be related to primary chemotherapy resistance and that of ABCB5 and ABCC5 to poor prognosis. Differential expression of resistance genes implicates that chemotherapy of hematologic malignancy patients should be personally customized and prognostically estimated according to the mRNA expression of resistance genes.

Key words : Drug resistance, Hematologic malignancy, ABC transporters