RESPONSE OF MAMMALIAN CELLS TO HALOGENATED PYRIMIDINES

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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.