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Comparative Effects on Growth and Tumorigenicity of Mouse Melanoma Cells by Thymidine and Its Analogs, 5-Ethyl- and 5-Bromodeoxyuridine¹

Cell Genetics Laboratory, Department of Obstetrics and Gynecology, Cornell University Medical College, New York, New York 10021 [S. S., R. F. B.], and University Eye-Clinic, University of Hamburg, 2 Hamburg 20, Federal Republic of Germany [K. K. G.]

Incorporation studies on pigmented clone B₅59 derived from B16 mouse melanoma reveal that, like 5-bromodeoxyuridine (BrdUrd), the new thymidine (TdR) analog, 5-ethyldeoxyuridine (EdUrd), enters cellular DNA. Cells grown for 24 hr in culture medium containing either nucleoside at 100 µM incorporate ethyluracil to the extent of 12% and bromouracil to 18% of total thymine. EdUrd produces biological effects entirely different from those of BrdUrd. Whereas EdUrd at 10 µM is toxic and renders most of the cell population irreversibly nonviable, at the same concentration BrdUrd can support growth for at least 13 generations and the population can revert to normal viability and morphology upon growth in normal medium. Cells grown in EdUrd continue to produce melanin, in contrast to BrdUrd-grown cells. Unlike TdR, EdUrd in equimolar combination with BrdUrd fails to prevent the characteristic effects of BrdUrd in B₅59 cells with respect to melanin, morphology, and tumorigenicity. TdR in equimolar combination with EdUrd overrides its effects, and cells maintain the characteristics of untreated cells. The negligible degree of incorporation of EdUrd when present in equimolar quantities with either BrdUrd or TdR explains its lack of effect in these combinations, indicating that incorporation of EdUrd into DNA is essential for its biological properties. Uptake of [³H]TdR and [³H]uridine into DNA and RNA, respectively, is greatly diminished in melanoma cells grown 48 hr in EdUrd (10 µM), which may well account for its toxicity to these cells. These precursors are normally incorporated into cells grown in BrdUrd under the same conditions, which probably explains their ability to grow at near-normal rates. [³H]Leucine uptake into the protein of B₅59 cells is normal in the presence of both EdUrd and BrdUrd.

EdUrd injected i.p. into mice daily for 12 days at the equivalent of 400 mg/kg of body weight does not prevent tumor growth when animals are given s.c. inoculations of 4 x 10⁵ melanoma cells on the 1st day of treatment. This lack of in vivo effectiveness appears to be due to the rapid metabolism and clearance of EdUrd in mice.

These data about EdUrd, a new TdR analog, and its comparison to related compounds in a well-studied tumor system may help form the basis for future experimental work, including the study of its possible use in treatment by injection or infusion into superficial skin tumors.

¹ This work was supported by USPHS Grant CA10095, National Cancer Institute, NIH.

² To whom requests for reprints should be addressed.

Received 8/26/76. Accepted 6/13/77.