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Modulation of IdUrd-DNA Incorporation and Radiosensitization in Human Bladder Carcinoma Cells¹

Department of Human Oncology, University of Wisconsin, Madison, Wisconsin 53792 [K. A. K., E. M. M., T. J. K.] and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 [M. A. V.-P.]

5'Amino-5'-deoxythymidine (5'-AdThd) has been demonstrated previously to antagonize dTTP-mediated feedback inhibition of purified thymidine kinase from 647V, a human bladder cancer cell line. Low concentrations of 5'-AdThd (3–30 µM) have also been shown to stimulate cellular uptake of iododeoxyuridine (IdUrd) in 647V cells at clinically relevant IdUrd concentrations (2 µM). We report that the combination of 30 µM 5'-AdThd plus 2 µM IdUrd results in a significant increase of IdUrd replacement of thymidine (dThd) (18%) in the DNA of 647V cells over that obtained by exposure to 2 µM IdUrd alone (7.9%). However, increasing the 5'-AdThd concentration to 300 µM inhibited the incorporation of IdUrd into DNA (3%). IdUrd-induced radiosensitization of 647V cells, as measured by clonogenic survival, was enhanced by coincubation with 30 µM 5'-AdThd, while 300 µM 5'-AdThd reduced the IdUrd radiosensitization. Additionally, radiation-induced single strand break generation when IdUrd was incorporated into 647V DNA, as measured by rapid alkaline elution, was also enhanced by coincubation with 30 µM 5'-AdThd, while 300 µM 5'-AdThd resulted in a decrease in the number of single strand breaks produced. In T24, another bladder cancer cell line, and SV-HUC-TT1, a tumorigenic cell line derived from SV-HUC, 3–10 µM 5'-AdThd was also able to enhance IdUrd replacement of dThd in DNA. However, no stimulation of dThd replacement by 5'-AdThd occurred in SV-HUC, a prototypic "normal" bladder urothelial cell line. Since 5'-AdThd is not a substrate for mammalian thymidine kinase and has little or no cytotoxicity in vitro and in vivo, it may be a selective modulator of IdUrd radiosensitization of human bladder carcinoma and should be tested in vivo.

¹ Supported in part by NCI Grant 50595 and by the Margaret and Donald Anderson Professorship.

² To whom requests for reprints should be addressed, at Department of Human Oncology, University of Wisconsin, Clinical Cancer Center, 600 Highland Avenue, K4/312 Madison, WI 53792.

Received 12/18/89. Revised 5/ 2/90.

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