From: Pharmacogene regulatory elements: from discovery to applications
Gene/miRNA | Drug | Comments | References |
---|---|---|---|
Promoters | Â | Â | Â |
MGMT | Temozolomide | Promoter methylation of the gene encoding O-6-methylguanine-DNA methyltransferase (MGMT) is associated with treatment outcome in patients with glioblastoma multiforme and anaplastic astrocytoma treated with temozolomide | |
UGT1A1 | Irinotecan | The UGT1A1*28 polymorphism (insertion of a seventh 'TA' repeat in the UGT1A1 promoter) leads to lower UGT1A1 expression levels, causing lower clearance of the active irinotecan metabolite, SN-38. This results in severe side effects, such as diarrhea and neutropenia | |
VKORC1 | Anticoagulant | A common promoter variant in VKORC1, -1639G>A (rs17878363), has significant implications for dosing algorithm of anticoagulant response. Patients with the variant G require higher dose of warfarin and have lower response to acenocoumarol | |
Enhancers | Â | Â | Â |
SLCO1A2 | Methotrexate | A screen of ECRs in the vicinity of nine pharmacologically relevant membrane transporters identified several enhancers, notably a region in the first intron of SLCO1A2. Common SNPs within this region were linked to reduced SLCO1A2 mRNA levels (rs4148981C>T) and methotrextate clearance (rs11045981 T>G) | [3] |
miRNAs | Â | Â | Â |
miR-24 | Methotrexate | A naturally occurring SNP near the miR-24 binding site in the 3' UTR of human DHFR (829C>T) interfered with miR-24 function and resulted in DHFR overexpression and methotrexate resistance | [73] |
miR-27a and miR-451 | Doxorubicin | P-glycoprotein, encoded by ABCB1, causes resistance in cancer cells to multiple chemotherapeutics, and can be activated by miR-27a and miR-451. Antagonizing these miRNAs results in increased uptake of doxorubicin | [71] |
miR-27b | Cyclophosphamide | Overexpression of miR-27b in PANC1cells downregulated CYP3A4 and led to cyclophosphamide resistance | |
miR-200b/200c/429 family | Cisplatin | A polymorphism (rs1045385) within the 3' UTR of TFAP2 prevents binding of this family of miRNAs, leading to higher levels of its product, transcription factor AP-2α. This variant allows drugs that induce AP-2α, such as cisplatin, to more effectively inhibit cancer cell growth | [4] |