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Variability of 5-Bromo-2'-deoxyuridine Incorporation into DNA of Human Glioma Cell Lines and Modulation with Fluoropyrimidines¹

College of Pharmacy, Departments of Pharmacology, Internal Medicine, Neurology, and Radiation Oncology, The University of Michigan Medical School, Ann Arbor, Michigan 48109

Human glioma-derived cell lines were found to vary in their ability to incorporate the radiosensitizer 5-bromo-2'-deoxyuridine (BrdUrd) into DNA after one cell doubling. The U-251 cell line was the best incorporator of BrdUrd, whereas U-118 and D-54 demonstrated poor incorporation with respective C₅₀ (BrdUrd concentration required for 50% of the maximum amount of BrdUrd incorporation into DNA) values of 2.8- and 6-fold greater than that of U-251 (P < 0.001). Modulation of radiosensitizer uptake into DNA could be achieved using the thymidylate synthase inhibitors 5-fluorouracil or 5-fluoro-2'-deoxyuridine (FdUrd). Incorporation into U-251 cells increased only slightly in the presence of the fluoropyrimidines. The BrdUrd concentration required for 50% of the maximum amount of BrdUrd incorporation into DNA changed (P < 0.001) from 1.8 ± 0.11 µM (SD) in the absence of a modulator to 1.1 ± 0.09 or 1.1 ± 0.16 µM in the presence of 10 µM 5-fluorouracil or 5 nM FdUrd, respectively. The D-54 cell line, which was the worst incorporator of BrdUrd, was found to have an extensive amount of BrdUrd into DNA following biomodulation. The C₅₀ in the absence of modulation was 7.3 ± 1.3 µM, which was reduced (P < 0.001) to 0.62 ± 0.04 and 0.32 ± 0.13 µM, respectively, in the presence of 10 µM 5-fluorouracil and 5 nM FdUrd. This represents a 12- to 22-fold reduction in the concentration of radiosensitizer required to achieve the same level of BrdUrd incorporation into DNA. Furthermore, this enhancement of BrdUrd DNA incorporation seen in the presence of the fluoropyrimidines is observed at clinically achievable concentrations. The degree of radiosensitization was solely dependent upon the amount of BrdUrd incorporated into DNA. D-54 cells grown in the presence of 0.18 µM BrdUrd plus 5 nM FdUrd or 2.8 µM BrdUrd alone yielded a similar level of BrdUrd incorporation into DNA and radiosensitization, though a 15-fold lower BrdUrd concentration was used in the presence of FdUrd. The combined use of a radiosensitizer with a fluoropyrimidine may overcome poor incorporation of BrdUrd into DNA that may exist among resistant subpopulations of cells within malignant glioma.

¹ This research was supported by Grant PO1-CA42761 from the National Cancer Institute.

Received 11/13/89. Accepted 11/ 6/90.

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