RESPONSE OF MAMMALIAN CELLS TO HALOGENATED PYRIMIDINES

当某些卤代嘧啶类化合物，如溴脱氧尿苷 (BrdUrd)和碘脱氧尿苷(IdUrd)被结合到 细胞DNA，细胞对电离辐射变得更加敏感 化疗药物。这一观察结果导致了几个临床 多年来和最近在NCI进行的研究，以评估 IdUrd可实现肿瘤的选择性增敏 输液后进行放射治疗。一个重要的问题出现在 这些关于药物在多大程度上 被整合到细胞中。工作继续开发技术，以 定量IdUrd在肿瘤和正常组织中的掺入。这个 IDUrd单抗在流式细胞术中被证明是有用的 关于准确预测标签指数的研究(比例 处于S期的细胞)，实验室目前正在参与(与 临床IdUrd研究)在评估这一潜在的重要 临床参数。未来的研究将涉及到图像分析 肿瘤切片以了解空间标记模式 在肿瘤内。肿瘤细胞中IdUrd替换的定量研究 DNA正在进行中；然而，由于肿瘤细胞的异质性，精确 这个变量很难量化。我们一直在工作 与模型啮齿动物肿瘤系统合作，试图解决分类问题 临床标本评估前的参数。最后， 使用半自动细胞培养试验(MTT)，我们已经建立了 诸如IdUrd之类的敏感者可以很容易地使用 这个化验结果。如此大规模的筛查应该允许进行评估 一种新型卤化嘧啶增敏剂。

When certain halogenated pyrimidines such as bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd) are incorporated into cellular DNA, cells become more sensitive to ionizing radiation and chemotherapy drugs. This observation has led to several clinical studies over the years and recently at the NCI to evaluate whether selective sensitization of tumors could be achieved by IdUrd infusion followed by radiation. An important question arises in these studies regarding the extent to which the drug is incorporated into cells. Work continues to develop techniques to quantify IdUrd incorporation into tumor and normal tissues. The IdUrd monoclonal antibody has proven useful in flow cytometry studies to accurately predict the labeling index (proportion of cells in S phase) and the laboratory is currently involved (with the clinical IdUrd study) in assessing this potentially important clinical parameter. Future studies will involve image analysis of tumor sections to gain insight as to spatial labeling patterns within the tumor. Quantitation of IdUrd replacement in tumor cell DNA is ongoing; however, due to tumor cell heterogeneity precise quantitation of this variable is difficult. We have been working with model rodent tumor systems in an attempt to work out sorting parameters prior to evaluation of clinical specimens. Lastly, using a semi-automated cell culture assay (MTT) we have established that sensitizers such as IdUrd can be easily be identified using this assay. Such large scale screening should allow for evaluation of new halogenated pyrimidine sensitizers.