Abstract
BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = −0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = −0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation.
Highlights
In 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters
In earlier studies, we found in patient tumor samples that IHC scores for the copper/platinum transporter CTR1 increased with increasing time from exposure to last prior therapy [40], and we interpreted this as possible evidence that prior therapy might induce crossresistance to platinums by downregulating CTR1, other explanations for our CTR1 observation are possible
We noted that tumor CTR1 IHC scores correlated inversely with long interspersed nuclear element 1 (LINE1) methylation, and that tumor CTR1 IHC scores increased after therapy with the DNA demethylating agent decitabine [40]
Summary
In 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Deficiency of factors required for drug uptake and activation might directly potentiate resistance by reducing the amount of active drug in a cell, but could have a secondary effect, in that these transporters may play a role in uptake and cellular metabolism of nutrients Deficiency in these factors could reduce the rate of tumor cell division, and quiescent cells are generally more resistant to chemotherapy than are actively dividing cells [1,2,4]. Promoter hypermethylation is one mechanism by which gene expression may be downregulated, and DNA methylation could play a role in underexpression of factors required for drug efficacy [8,9,10,11,12,13,14,15,16,17,18]. Several genes may be hypermethylated in resistant cell lines [14,15] or tumors [18]
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