This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kuo, M.-L. Articles by Kinsella, T. J. Search for Related Content PubMed PubMed Citation Articles by Kuo, M.-L. Articles by Kinsella, T. J.

The Interaction of Hydroxyurea and Iododeoxyuridine on the Radiosensitivity of Human Bladder Cancer Cells¹

Departments of Human Oncology [M-L. K., K. A. K., T. J. K.] and Biostatistics [M. J. L.], University of Wisconsin Medical School, Madison, Wisconsin 53792

Biochemical modulation of iododeoxyuridine (IdUrd) incorporation into the DNA of tumor cells is a potential clinical strategy to enhance radiosensitivity and to simultaneously differentiate the sensitivity of rapidly proliferating tumor cells and more slowly proliferating adjacent normal tissues to radiation. The interactions of hydroxyurea (HU) and IdUrd were studied in a human bladder cancer cell line, 647V. Exposure of exponentially growing 647V cells to HU concentrations of 10–100 µM for one cell population doubling (24 h) resulted in no cytotoxicity as assessed by clonogenic survival. Flow cytometric analysis showed a significant increase in an early S-phase population after a 12-h exposure but a return to a normal cell cycle distribution after a 24-h exposure to 100 µM HU. Incorporation of IdUrd into DNA was increased 2-fold by coincubation with HU (100 µM) and a clinically achievable concentration of IdUrd (2 µM) for 24 h. To elucidate the mechanism of modulation, IdUTP pools were compared in 647V cells treated with 2 µM IdUrd with or without 100 µM HU. A 2-fold increase in IdUTP pools was evident within 2 h when this drug combination was used. With the use of multivariate statistical analysis, the radiosensitivity of 647V cells was compared after a 24-h exposure to various concentrations of IdUrd (0 and 2 µM) and HU (0, 10, and 100 µM). A 24-h exposure to 100 µM HU alone or to 2 µM IdUrd alone before irradiation resulted in significant (P < 0.02) radiosensitization with sensitizer enhancement ratios of 1.15 and 1.27, respectively. A 24-h exposure to 100 µM HU + 2 µM IdUrd resulted in even more significant (P = 0.0001) radiosensitization, which was found to be a greater than additive response (sensitizer enhancement ratio, 1.76 observed compared with 1.37 expected). No radiosensitization was found with a 12-h exposure to 100 µM HU alone. The mechanism of biochemical modulation of IdUrd by a noncytotoxic dose of HU is proposed as increasing the IdUTP pools by stimulating enzymes in the thymidine salvage pathway and subsequently enhancing IdUrd incorporation and radiosensitization.

¹ Supported in part by NIH Grant CA50595 (T. J. K.) and the Margaret and Donald Anderson Professorship.

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

Received 11/ 4/95. Accepted 5/ 3/96.

This article has been cited by other articles:

				D. S. Shewach and T. S. Lawrence Antimetabolite Radiosensitizers J. Clin. Oncol., September 10, 2007; 25(26): 4043 - 4050. [Abstract] [Full Text] [PDF]

				C. A. Barker, W. E. Burgan, D. J. Carter, D. Cerna, D. Gius, M. G. Hollingshead, K. Camphausen, and P. J. Tofilon In vitro and In vivo Radiosensitization Induced by the Ribonucleotide Reductase Inhibitor Triapine (3-Aminopyridine-2-Carboxaldehyde-Thiosemicarbazone). Clin. Cancer Res., May 1, 2006; 12(9): 2912 - 2918. [Abstract] [Full Text] [PDF]