Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104.
Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104.
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在鼠和人类白血病模型中明显缺氧：缺氧激活前药PR-104的高疗效。
DOI：
10.1371/journal.pone.0023108
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Konopleva M
中科院分区：
文献类型：
--
作者：
Benito J;Shi Y;Szymanska B;Carol H;Boehm I;Lu H;Konoplev S;Fang W;Zweidler-McKay PA;Campana D;Borthakur G;Bueso-Ramos C;Shpall E;Thomas DA;Jordan CT;Kantarjian H;Wilson WR;Lock R;Andreeff M;Konopleva M
最近的研究表明，白血病细胞与骨髓微环境之间的相互作用促进了白血病细胞的存活，并导致了对抗白血病药物的耐药性。有证据表明，骨髓微环境中含有为造血细胞提供生存优势的缺氧区。在本研究中，我们研究了白血病骨髓中的低氧是否有助于骨髓微环境的保护作用。我们观察到移植了急性淋巴细胞白血病(ALL)细胞的免疫缺陷小鼠的缺氧性BM区显著扩大。与这一发现一致的是，我们发现低氧促进了各种ALL衍生细胞系的化疗耐药性。这些发现建议使用低氧激活的前体药物来消除低氧环境中的白血病细胞。使用几种异种移植模型，我们证明了给予低氧激活的二硝基苯甲酰胺芥末PR-104延长了注射原代急性淋巴细胞白血病细胞的免疫缺陷小鼠的生存时间并降低了白血病负担。综上所述，这些发现有力地表明，靶向低氧治疗白血病骨髓是可行的，并可能显著改善白血病的治疗。
Recent studies indicate that interactions between leukemia cells and the bone marrow (BM) microenvironment promote leukemia cell survival and confer resistance to anti-leukemic drugs. There is evidence that BM microenvironment contains hypoxic areas that confer survival advantage to hematopoietic cells. In the present study we investigated whether hypoxia in leukemic BM contributes to the protective role of the BM microenvironment. We observed a marked expansion of hypoxic BM areas in immunodeficient mice engrafted with acute lymphoblastic leukemia (ALL) cells. Consistent with this finding, we found that hypoxia promotes chemoresistance in various ALL derived cell lines. These findings suggest to employ hypoxia-activated prodrugs to eliminate leukemia cells within hypoxic niches. Using several xenograft models, we demonstrated that administration of the hypoxia-activated dinitrobenzamide mustard, PR-104 prolonged survival and decreased leukemia burden of immune-deficient mice injected with primary acute lymphoblastic leukemia cells. Together, these findings strongly suggest that targeting hypoxia in leukemic BM is feasible and may significantly improve leukemia therapy.
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影响因子：
20.3
作者：
Chitteti, Brahmananda R.;Cheng, Ying-Hua;Srour, Edward F.
通讯作者：
Srour, Edward F.
影响因子：
3.2
作者：
Houghton, Peter J.;Lock, Richard;Carol, Hernan;Morton, Christopher L.;Phelps, Doris;Gorlick, Richard;Kolb, E. Anders;Keir, Stephen T.;Reynolds, C. Patrick;Kang, Min H.;Maris, John M.;Wozniak, Amy W.;Gu, Yongchuan;Wilson, William R.;Smith, Malcolm A.
通讯作者：
Smith, Malcolm A.
影响因子：
11.2
作者：
Jin, Yanli;Lu, Zhongzheng;Pan, Jingxuan
通讯作者：
Pan, Jingxuan
影响因子：
11.2
作者：
Guise, Christopher P.;Abbattista, Maria R.;Patterson, Adam V.
通讯作者：
Patterson, Adam V.
影响因子：
20.3
作者：
Neering, Sarah J.;Bushnell, Timothy;Jordan, Craig T.
通讯作者：
Jordan, Craig T.