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10.1158/1078-0432.CCR-14-3378 http://scihub22266oqcxt.onion/10.1158/1078-0432.CCR-14-3378 C4818660!4818660!26603259     free     free     free Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Clin+Cancer+Res 2016 ; 22 (7): 1687-98 Nephropedia Template TP {{tp|p=26603259|t=2016. Hypoxia-activated prodrug TH-302 targets hypoxic bone marrow niches in pre-clinical leukemia models |pdf=|usr=}}{{26603259}} gab.com Text Hypoxia-activated prodrug TH-302 targets hypoxic bone marrow niches in pre-clinical leukemia models JO: Clin Cancer Res http://www.kidney.de/pget.php?&tw=1&pmid=26603259 #FOAvip Purpose: to characterize the prevalence of hypoxia in the leukemic bone marrow (BM), its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia activated prodrug TH-302 in leukemia models. Experimental design: hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine AML model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated pro-drug TH-302 was examined in the in vitro and in vivo leukemia models. Results: Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared to healthy control mice, suggesting metabolic re-programming of hypoxic BM niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a ?hypoxia index? compared to samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models and reduced the leukemia stem cell pool in vivo. In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater anti-leukemia effects than either drug alone. Importantly, residual leukemic BM cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. Conclusions: These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. Twit Text FOAVip Hypoxia-activated prodrug TH-302 targets hypoxic bone marrow niches in pre-clinical leukemia models ????Clin Cancer Res http://www.kidney.de/pget.php?&tw=1&pmid=26603259 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26603259 #FOAvip English Wikipedia <ref>{{Cite pmid|26603259}}</ref> Hypoxia-activated prodrug TH-302 targets hypoxic bone marrow niches in pre-clinical leukemia models #MMPMID26603259 Benito J; Ramirez M; Millward NZ; Velez J; Harutyunyan K; Lu H; Shi Y; Matre P; Jacamo R; Ma H; Konoplev S; McQueen T; Volgin A; Protopopova M; Mu H; Lee J; Bhattacharya P; Marszalek JR; Davis RE; Bankson J; Cortes J; Hart CP; Andreeff M; Konopleva M Clin Cancer Res 2016[Apr]; 22 (7): 1687-98 PMID26603259show ga Purpose: to characterize the prevalence of hypoxia in the leukemic bone marrow (BM), its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia activated prodrug TH-302 in leukemia models. Experimental design: hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine AML model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated pro-drug TH-302 was examined in the in vitro and in vivo leukemia models. Results: Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared to healthy control mice, suggesting metabolic re-programming of hypoxic BM niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a ?hypoxia index? compared to samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models and reduced the leukemia stem cell pool in vivo. In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater anti-leukemia effects than either drug alone. Importantly, residual leukemic BM cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. Conclusions: These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. äHypoxia-activated prodrug TH-302 targets hypoxic bone marrow niches in(epmc).pdf DeepDyve Pubget Overpricing