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RADIO AND CHEMO SENSITIZATION DEPENDENCE ON OXYGEN

放射和化学增敏对氧气的依赖性

基本信息

批准号：
3446480
负责人：
LAURIE A ROIZIN-TOWLE
金额：
$ 6.04万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-07-01 至 1986-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3446480
关键词：
N phosphonoacetyl L aspartate bleomycin cell membrane cis platinum compound combination cancer therapy cytotoxicity drug adverse effect hypoxia ion transport melphalan membrane permeability radiation sensitivity respiratory oxygen tissue /cell culture

项目摘要

The possibility that hypoxic cells limit the successful control of solid tumors by x-rays has been recognized by radiation oncologists for more than 25 years. The realization that hypoxia may be a limiting factor in chemotherapy is much more recent. Attempts to overcome the resistance of hypoxic cells to radiotherapy have led to the development of "hypoxic cell sensitizers", drugs that mimic oxygen and interact with radiation to specifically increase the sensitivity of hypoxic cells. These sensitizers preferentially kill hypoxic cells with a time-dependent cytotoxicity. This cytotoxicity is the basis of the "preincubation effect" where prolonged exposure of hypoxic cells to sensitizing drugs enhances their killing by radiation and cancer chemotherapeutic agents. Exploitation of the preincubation effect of these agents can be clinically advantageous where lower doses of sensitizer can be used systemically to enhance the action of radiation and chemotherapy drugs. The role of oxygen in this potentiation is important because it may help to explain differences found between animal and cell culture systems, and may mimic the intermediate levels of oxygen expected to be found in solid tumors. Determination of the K factor for radio- and chemo- sensitization would be of practical value in evaluating the most effective use of these sensitizing compounds. Experiments with mammalian cells of hamster and human origin are planned to investigate and compare what levels of oxygen in a preincubation exposure result in radio- and chemo- sensitization. Cells pretreated with several 2 and 4-nitroimidazoles will be subsequently exposed to increasing doses of x-rays or Bleomycin, Cis-DDP, L-PAM, PALA, and BCNU. The plasma cell membrane will also be analyzed as a target of the preincubation effect by assaying for levels of Na, Kg Mg, and Ca-ATPase in pretreated cells. Use of the preincubation effect, to enhance the killing of hypoxic cells resistant to drug and radiation therapy, can make a significant contribution in the treatment of solid tumors.

低氧细胞限制固体的成功控制的可能性 X射线引起的肿瘤已经被放射肿瘤学家认识到超过 25年。意识到低氧可能是一个限制因素化疗要晚得多。试图克服的阻力低氧细胞对放射治疗的作用已导致“低氧细胞”的发展 “增敏剂”，模拟氧气并与辐射相互作用的药物特别提高缺氧细胞的敏感度。这些感光剂优先杀死低氧细胞，具有时间依赖性的细胞毒性。这细胞毒性是“预孵化效应”的基础。低氧细胞暴露于致敏药物可通过以下途径增强其杀伤力放射和癌症化疗药物。利用这些资源在以下情况下，这些试剂的预孵化效果可能是临床上有利的较低剂量的增敏剂可全身使用，以增强放射和化疗药物。氧在这种增强作用中的作用是很重要的，因为它可能有助于解释动物和细胞培养系统，并可能模仿预计在实体肿瘤中会发现氧气。K因子的测定对于放射和化学敏化将在评估这些致敏化合物的最有效使用。计划用仓鼠和人类来源的哺乳动物细胞进行实验调查并比较预孵化暴露中的氧气水平导致放射和化学敏感化。用几个2 和4-硝基咪唑随后将暴露于越来越多的 X线或博莱霉素、顺铂、L-PAM、PALA和BCNU。浆细胞膜也将作为预孵化效果的目标进行分析测定预处理细胞中钠、公斤镁和钙-三磷酸腺苷酶的水平。使用对预孵化作用，增强对低氧细胞的杀伤作用对药物和放射治疗的抗药性，可以使在实体瘤治疗中的贡献。