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Microregional Heterogeneity of Non-Protein Thiols in Cervical Carcinomas Assessed by Combined Use of HPLC and Fluorescence Image Analysis¹

Department of Medical Biophysics, Ontario Cancer Institute, Toronto, Ontario, M5G 2 M9 Canada [V. V., D. W. H.], and Departments of Medical Oncology and Hematology [D. W. H.] and Oncologic Pathology [T. N., D. W. H.], Princess Margaret Hospital, Toronto, Ontario, M5G 2 M9 Canada

Under low oxygen conditions, non-protein thiols (NPSHs, non-protein sulfhydryls) can effectively compete for DNA radicals sites and hence represent a potentially important cause of radiation resistance in the clinic. Intra- and intertumoral heterogeneity of glutathione (GSH) and cysteine were assessed in cryostat sections of multiple biopsies obtained from 10 cervical carcinomas by the combined use of a sensitive high-performance liquid chromatography (HPLC) method and a fluorescence image analysis technique to examine the spatial distribution of NPSHs in tumor tissue. Glutathione concentrations ranged from 1.98 to 4.42 mM; significant (1 mM) concentrations of cysteine, a more effective radioprotector than GSH, were found in some tumors. By HPLC, the intratumoral heterogeneity of NPSHs was relatively small compared with the intertumoral heterogeneity. The histochemical stain 1-(4-chloromercuryphenoylazo)-2-napthol (mercury orange), which binds to GSH and cysteine, was used to determine the spatial distribution of NPSHs in tumor tissue. A comparison of NPSH levels in serial cryostat sections showed a close correlation between NPSH values determined by HPLC and mercury orange fluorescence quantification. Using fluorescence image analysis, an 2-fold increase of NPSHs in tumor versus nonmalignant tissue was observed in the same section. Because some cervical carcinomas contain radiobiologically important levels of cysteine, agents that target the biochemical pathways maintaining tumor cysteine have therapeutic potential as adjuncts to radiotherapy in cervix cancer patients.

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