Abstract
BackgroundDemethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m2/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m2/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed.ResultsThirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from <0.25 to 5.8 μg/g tumor. The platinum concentration increased 3- to 18-fold. No correlation was found between CTR1 score and oxaliplatin level, which was found to have a trend toward correlation with progression-free survival.ConclusionsOxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0065-5) contains supplementary material, which is available to authorized users.
Highlights
Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance
Many factors contribute to chemotherapy resistance [7], flattening of the dose-response curve at higher drug doses suggests that a deficiency of certain cell
The study was terminated early because of limited funding for tumor biopsies following the recommendation of The Cancer Therapy Evaluation Program
Summary
Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. Oxaliplatin (a third-generation platinum compound) is recommended as a frontline therapy for Resistance to platinum-based chemotherapy can be caused by DNA hypermethylation, a critical epigenetic process in cancer progression. Many factors contribute to chemotherapy resistance [7], flattening of the dose-response curve at higher drug doses suggests that a deficiency of certain cell-. Platinum-resistant cells have been shown to have hypermethylation of the MLH1 mismatch repair gene that is important in triggering platinum cytotoxicity [9] or a pleiotropic reduction in transporters [10,11] that is potentially reversible by a DNA methyltransferase inhibitor such as decitabine [12]. In a phase I clinical trial of the hypomethylating agent decitabine in patients with refractory solid tumors and lymphomas, administration of decitabine significantly increased CTR1 expression [14]
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