Diphtheria toxin-interleukin-3 fusion protein (DT388IL3) prolongs disease-free survival of leukemic immunocompromised mice
Diphtheria toxin-interleukin-3 fusion protein (DT388IL3) prolongs disease-free survival of leukemic immunocompromised mice
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DOI：
10.1038/sj.leu.2402744
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发表时间：
2003-01-01
期刊：
影响因子：
11.4
通讯作者：
Frankel, AE
中科院分区：
文献类型：
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作者：
Black, JH;McCubrey, JA;Frankel, AE
新的融合蛋白DT（388）IL 3由白喉毒素（DT 388）的催化和易位结构域与人白细胞介素3（IL-3）的Met-His接头融合组成，在分化的人急性髓性白血病（AML）的体内模型中测试抗白血病功效。对六周龄雌性SCID小鼠进行350 cGy照射，24小时后接种2000万只（静脉注射，腹腔注射，或s.c.）用v-SRC癌基因转染的TF 1细胞，并经腹膜内处理，从24小时后开始，每天注射盐水、DT（388）IL 3（2 μ g）、DT（388）GMCSF（2 μ g）、DAB（389）IL 2（2 μ g）或阿糖胞苷（80 μ g）多达5次，或每周注射抗-CD 33-加利车霉素缀合物（5 μ g）两次。每天监测动物两次，处死濒死动物并进行尸检。对照动物的中位无病存活期（DFS）为37天（i. v.，n = 45），35天（i. p.，n = 20）和21天（s.c.，n = 20）。DT（388）IL 3治疗的静脉接种动物中，只有5/49（10%）死于白血病。静脉注射的中位DFS，腹腔注射和皮下注射肿瘤接种的动物通过融合蛋白处理分别延长至>120天、66天和31天（P < 0.001，= 0.0003，和= 0.0006）。皮下注射的中位DFS与对照组相比，其他活性抗白血病药物（DT（388）GMCSF、阿糖胞苷和抗CD 33-卡奇霉素）也使接种肿瘤的动物的存活时间延长了67%、172%和47%（P < 0.0001，
The novel fusion protein DT(388)IL3, composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused with a Met-His linker to human interleukin 3 (IL-3), was tested for anti-leukemia efficacy in an in vivo model of differentiated human acute myeloid leukemia (AML). Six-week-old female SCID mice were irradiated with 350 cGy, inoculated 24 h later with 20 million (i.v., i.p., or s.c.) TF1 cells transfected with the v-SRC oncogene, and treated i.p., starting 24 h later, with up to five daily injections of saline, DT(388)IL3 (2 mug), DT(388)GMCSF (2 mug), DAB(389)IL2 (2 mug), or cytarabine (80 lAg) or two weekly injections of anti-CD33-calicheamicin conjugate (5 mug). Animals were monitored twice daily, and moribund animals killed and necropsied. Control animals had a median disease-free survival (DFS) of 37 days (i.v., n = 45), 35 days (i.p., n = 20), and 21 days (s.c., n = 20), respectively. Only 5/49 (10%) of the DT(388)IL3 treated i.v. inoculated animals died with leukemia. Median DFS with i.v., i.p. and s.c. tumor inoculated animals was prolonged by fusion protein treatment to >120 days, 66 days and 31 days (P < 0.001, = 0.0003, and = 0.0006), respectively. Median DFS with s.c. tumor inoculated animals was also prolonged by other active anti-leukemia agents (DT(388)GMCSF, cytarabine and anti-CD33-calicheamicin) relative to controls by 67%, 172% and 47% (P < 0.0001,