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• W1991513738 abstract "Background: TriN2755 is an alkylating agent currently under investigation in a phase-I study. Pharmacokinetic evaluation showed high inter-individual variability of the plasma concentration of its metabolite TriN3001. We speculate that differences in renal and metabolic clearance of TriN2755 and different expression of MGMT had contributed to the heterogeneous responses in xenograft models. We hypothesize that administration of TriN3001 improves predictability of drug levels and broadens the therapeutic window. In this study, we investigated the anti-tumor effect of TriN3001 given intraperitoneally after treatment of TriN2755 and temozolomide (TEM) in the colon-cancer cell line SW-480. Material and Methods: The in vitro effect of TriN2755 and 3001 on the proliferation of SW-480 was evaluated by IC50 determination. To study the in vivo efficacy, 5 × 106 cells of each cell line were inoculated in the flanks or back of nude mice. SW-480 mice were treated with TriN2755 (500mg/kg, biw, ip), TEM (120mg/kg qd×5, po) and NaCl as control. Treatment stopped at day 24 for interim-analysis. Mice were then being treated once daily with TriN3001 at a dose of 67,6mg/kg (low dose, former TriN), 100mg/kg (mid dose, former TEM) and 150mg/kg (high dose, former control) for another 16 to 20 days. Antitumor activity was assessed as (i) tumor volume inhibition relative to a vehicle control group for TriN2755 and (ii) change in tumor size from start of treatment for TriN3001. Tolerability was analysed by recording mortality, body weight loss and gross necropsy. Plasma and tissues were collected for pharmacokinetic and -dynamic evaluation. Results: In vitro, TriN2755 and 3001 and TEM displayed only weak growth inhibition with IC50 values of >3mM, 1mM and 1.2mM respectively. Nevertheless, in vivo T/C values of 40% (TriN2755) and 29% (TEM) were achieved at day 21. TEM and TriN2755 showed acceptable tolerability with no mortality and maximum body weight losses of 7% (TriN2755) and 10% (TEM). Daily administration of TriN3001 lead to remission in all mice, ranging from 66mm3 (30,3%) in the low, 77,6mm3 (23,1%) in the mid and 224mm3 (29,4%) in the high dose. TriN3001 and its metabolites were detectable in plasma and all tissues. In tumors, depletion of the repair enzyme MGMT increased over time with 60% depletion at 90min. Body weight loss didn9t appear in the mid but in the low (−6%) and high (−20%) dose. At the end of treatment, thrombocytes and erythrocytes are within the reference range, lymphocytes lower and granulocytes higher than the reference. Conclusions: Daily application of TriN3001 led to remission of SW-480 tumors in mice independent from magnitude of tumor size. The treatment caused a marked depletion of MGMT protein in tumors. A second metabolite, with an IC50 value about 10fold lower than TriN3001 may have contributed to the efficacy. Further PK/PD data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C119." @default.
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• W1991513738 date "2011-11-12" @default.
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• W1991513738 title "Abstract C119: Depletion ofO6-methylguanine DNA methyltransferase (MGMT) by TriN3001 leads to remission in SW-480 xenograft mice." @default.
• W1991513738 doi "https://doi.org/10.1158/1535-7163.targ-11-c119" @default.
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