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- W4361951878 abstract "<div>Abstract<p><b>Purpose:</b> To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI).</p><p><b>Experimental Design:</b> Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. <i>In vivo</i> activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). <i>SLFN11</i> expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting.</p><p><b>Results:</b> Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/dose) achieved complete responses maintained for >100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High <i>SLFN11</i> expression has been reported to correlate with sensitivity to DNA damaging agents; median <i>SLFN11</i> mRNA expression was >100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with <i>SLFN11</i> mRNA expression in 20 EFT cell lines.</p><p><b>Conclusions:</b> In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if <i>SLFN11</i> expression can serve as a biomarker to predict nal-IRI clinical activity are warranted. <i>Clin Cancer Res; 21(5); 1139–50. ©2015 AACR</i>.</p></div>" @default.
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- W4361951878 date "2023-03-31" @default.
- W4361951878 modified "2023-09-25" @default.
- W4361951878 title "Data from Activity of MM-398, Nanoliposomal Irinotecan (nal-IRI), in Ewing's Family Tumor Xenografts Is Associated with High Exposure of Tumor to Drug and High <i>SLFN11</i> Expression" @default.
- W4361951878 doi "https://doi.org/10.1158/1078-0432.c.6524660.v1" @default.
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