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DNA in Situ Sensitivity to Denaturation in Bladder Cancer and Its Correlation with Tumor Stage¹

Memorial Sloan-Kettering Cancer Center Departments of Pathology [Z. D., E. H., M. K., M. R. M.], and Surgery, Division of Urology [P. R. B., W. R. F.], New York, New York 10021

DNA content and sensitivity of DNA in situ to denaturation by acid were analyzed by flow cytometry of cell nuclei freshly isolated from the bladder tumors of 32 patients and were compared with normal urothelium of 8 subjects. DNA sensitivity to denaturation was assessed in RNase treated cells by acridine orange metachromasia following partial denaturation with hydrochloric acid; the extent of denatured DNA is given as an index (t), representing the ratio of single stranded to total DNA per nucleus.

Of the low stage tumors (papillomas, Ta, Tis, T1) 11 of 18 (61%) were aneuploid. Of the high stage tumors (T2 and T3a) 11 of 14 (79%) were aneuploid. DNA in nuclei of normal transitional epithelium was very sensitive to denaturation, as was papilloma, characterized by nuclear t indices of 0.73 ± 0.01 (SD) and 0.73 ± 0.04, respectively. Nuclear DNA of noninvasive carcinomas (Ta, Tis) was significantly more resistant to denaturation (t = 0.69), and DNA of invasive carcinomas was most resistant, ranging from t = 0.61 (T₁ tumors) to t = 0.59 (T₂ tumors) to t = 0.57 (T₃ tumors).

High stage tumors as a group (T₂, T₃) had significantly different (lower) t values than low stage tumors (Ta, Tis, T1). In model cell culture systems it is known that a decrease in t index, i.e., greater resistance to denaturability, occurs as cells transit from resting phase into the cell cycle. Whether the t index can be used to estimate resting vesus cycling cells of human tumors is still speculative; changes in DNA denaturability also are known to occur with changes in chromatin structure during cell differentiation and in transformation. However, the empirical relationship between t index and tumor stage, of itself, may prove clinically useful in identifying more advanced and perhaps more aggressive tumors.

¹ Supported in part by National Cancer Institute Grants R01-CA 14134 and UO-CA 41021.

Received 11/ 6/89. Accepted 9/17/90.