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ROOT EFFECT HEMOGLOBINS IN CANCER THERAPY

血红蛋白在癌症治疗中的根本效应

基本信息

批准号：
2769828
负责人：
JAMES J FISCHER
金额：
$ 30.5万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-06 至 2000-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2769828
关键词：
Bohr effect alternatives to animals in research hemoglobin hypoxia laboratory mouse laboratory rat liposomes neoplasm /cancer radiation therapy oxygen microelectrode oxygen therapy radiation resistance radiobiology rhabdomyosarcoma trout /salmon

项目摘要

DESCRIPTION: The purpose of this project is to investigate the potential usefulness of Root effect hemoglobins to improve tumor oxygenation for cancer therapy. Root effect hemoglobins are found in some fish. The Root effect is essentially an exaggerated Bohr effect wherein oxygen affinity is greatly decreased at acid pH. Root effect hemoglobins serve as pressure transducers. Under appropriate circumstances it is possible to load hemoglobin at ambient oxygen pressure, i.e. a human or mammal breathing ambient air, and to deliver oxygen under vastly increased, even hyperbaric, pressure in acidic tissues. Hemoglobin Ill of the American rainbow trout S. gairdneri will be used for this work. At pH 7.4 it demonstrates an oxygen-hemoglobin dissociation curve similar to that of most mammalian hemoglobins. Depending upon the exact experimental conditions, the value of P(50), the partial pressure at which hemoglobin is one-half saturated, at pH circa 6.8 can be as high as 1,000 torr. Two well established rodent tumor systems, the EMT6 mouse mammary carcinoma in BALB/C Rw mice and the BA1112 rhabdomyosarcoma in WAG/Rij rats, which have been shown to contain hypoxic cells resistant to the effects of ionizing radiation, will be used for this study. Trout III hemoglobin will be administered to tumor bearing animals either as stroma-free hemoglobin or as hemoglobin repackaged in liposomes or intact red blood cells. Its effect on tumor hypoxia and radiobiological response will be investigated using oxygen microelectrode measurements and the classic methods for determining "radiobiological hypoxic fraction" including the in vivo-in vitro paired radiation clonogenic cell survival method, tumor regrowth delay, and long-term local tumor control. Preliminary experiments including a direct comparison of the effects of red blood encapsulated Root effect and non-Root effect hemoglobin on tumor oxygenation using the paired radiation cell survival method with the BA1112 rhabdomyosarcoma have demonstrated the potential of this approach. Radiation response will be determined for single radiation treatments and for fractionated courses of radiation therapy. Parallel studies will investigate the effects of the Root effect hemoglobin on the radiation reactions of selected normal tissues including skin, bone regrowth, and the hematopoietic system.

描述：该项目的目的是调查潜在的根效应血红蛋白在改善肿瘤氧合方面的作用癌症治疗。根效应血红蛋白在某些鱼类中发现。根这种效应本质上是一种夸大的玻尔效应，其中氧亲和力被在酸性pH值下大大降低。根效应血红蛋白作为压力传感器在适当的情况下，可以加载在环境氧压下的血红蛋白，即人或哺乳动物呼吸环境空气，并提供氧气下大大增加，甚至高压，酸性组织中的压力。美国虹鳟血红蛋白III。 gairdneri将用于这项工作。在pH 7.4时，它显示出氧-血红蛋白解离曲线与大多数哺乳动物相似血红蛋白根据确切的实验条件， P（50），血红蛋白达到一半饱和时的分压，在pH 大约6.8可以高达1,000欧姆。两个良好建立的啮齿动物肿瘤系统，EMT 6小鼠乳腺癌 BALB/C Rw小鼠和WAG/Rij大鼠的BA 1112横纹肌肉瘤，已经显示含有耐缺氧细胞，电离辐射，将用于本研究。鳟鱼三号血红蛋白作为无基质血红蛋白或如血红蛋白重新包装在脂质体或完整的红细胞中。的影响对肿瘤缺氧和放射生物学反应的研究将使用氧微电极测量和经典的测定方法 “放射生物学低氧分数”，包括体内-体外配对放射克隆形成细胞存活方法，肿瘤再生长延迟，和长期局部肿瘤控制。初步实验包括直接红细胞包被Root效应与非Root效应的比较应用配对放射池研究血红蛋白对肿瘤氧合的影响 BA 1112横纹肌肉瘤的生存方法已经证明了这种方法的潜力。辐射反应将被确定为单次放射治疗和分次放射治疗疗法平行研究将调查根效应的影响血红蛋白对选定的正常组织的辐射反应，包括皮肤、骨骼再生和造血系统。