<div>Abstract<p>Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (<i>SLC22A4</i>; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analogue cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally related cytidine analogues, such as 2′deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside. Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogues are used in cancer treatment. <i>Cancer Res; 77(8); 2102–11. ©2017 AACR</i>.</p></div>
<p>This file contains supplementary information regarding materials and methods including: chemicals and reagents, early drug uptake, NCI60 correlation analysis, quantitative determination of ergothioneine, and culturing keratinocytes.</p>
<div>AbstractPurpose:<p>To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies.</p>Patients and Methods:<p>Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated.</p>Results:<p>In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; <i>P</i> < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f (<i>P</i> = 7e−4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f (<i>P</i> = 1e−4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f (<i>P</i> < 0.003). In exposure–toxicity analysis, a shorter time to development of grade 2–3 hand–foot skin reaction (HFSR) was associated with concurrent (<i>P</i> = 0.0015) but not with sequential (<i>P</i> = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib (<i>P</i> = 0.0004) and sorafenib N-oxide (<i>P</i> = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR.</p>Conclusions:<p>Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure–response relations for alternative dosing strategies to minimize skin toxicity.</p></div>
<div>AbstractPurpose:<p>To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies.</p>Patients and Methods:<p>Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated.</p>Results:<p>In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; <i>P</i> < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f (<i>P</i> = 7e−4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f (<i>P</i> = 1e−4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f (<i>P</i> < 0.003). In exposure–toxicity analysis, a shorter time to development of grade 2–3 hand–foot skin reaction (HFSR) was associated with concurrent (<i>P</i> = 0.0015) but not with sequential (<i>P</i> = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib (<i>P</i> = 0.0004) and sorafenib N-oxide (<i>P</i> = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR.</p>Conclusions:<p>Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure–response relations for alternative dosing strategies to minimize skin toxicity.</p></div>
<div>Abstract<p>Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (<i>SLC22A4</i>; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analogue cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally related cytidine analogues, such as 2′deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside. Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogues are used in cancer treatment. <i>Cancer Res; 77(8); 2102–11. ©2017 AACR</i>.</p></div>
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