Phase I study of azacitidine and oxaliplatin in patients with advanced cancers that have relapsed or are refractory to any platinum therapy
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- 作者：Apostolia M Tsimberidou ; Rabih Said ; Kirk Culotta ; Ignacio Wistuba…
- 关键词：DNA methylation ; Platinum resistance ; Copper/platinum transporter
- 刊名：Clinical Epigenetics
- 出版年：2015
- 出版时间：December 2015
- 年：2015
- 卷：7
- 期：1
- 全文大小：1,300 KB
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- 出版者：BioMed Central
- ISSN：1868-7083
文摘
Background 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. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (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. Results Thirty-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 Conclusions Oxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration.