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 Philips, F. S. Articles by Vidal, P. M. Search for Related Content PubMed PubMed Citation Articles by Philips, F. S. Articles by Vidal, P. M.

Hydroxyurea

I. Acute Cell Death in Proliferating Tissues in Rats¹

Division of Experimental Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, New York

Hydroxyurea induces karyorrhexis in intestinal crypts, bone marrow, and germinal centers of all lymphoid tissues within a few hr after injection. Acute, selective cytotoxic effects are limited to those tissues with high rates of cellular proliferation. The pathologic process is of short duration, and repair of tissue damage is rapid. Other hydroxamic acid derivatives induce similar lesions: N-hydroxyurethan, acetohydroxamic acid, N,O-diacetyl-N-methylhydroxylamine, and 1-methyl- and 1-ethyl-1-hydroxyurea. The lesions are not seen in rats given hydroxylamine or N-methylhydroxylamine.

The cytotoxic effects are related in time to the physiologic disposition of hydroxyurea. The agent is rapidly equilibrated throughout body water. Its concentration in plasma decays exponentially with half-lives of 65 min at levels above 150 µg/ml and of 35 min below 100 µg/ml. N-Hydroxyurethan and acetohydroxamic acid are disposed of in vivo at comparable rates. All 3 substances are excreted unchanged in urine and are also extensively metabolized. The close temporal relation between the build-up and repair of cytotoxic changes and the physiologic disposition suggests that the proximal biochemical defect produced by the hydroxamates is reversible.

Hydroxyurea induces an immediate inhibition of thymidine incorporation into the DNA of thymus and small intestine in rats. The inhibition is reversible; its duration varies directly with the dose of hydroxyurea. From information about tissue concentrations it can be concluded that the sensitivity of thymidine incorporation in intestine and thymus in vivo is close to that of HeLa cells in culture. The cytotoxic potency of hydroxyurea, N-hydroxyurethan, and acetohydroxamic acid in intact rats is in proportion to their relative activity in inhibiting thymidine incorporation in HeLa cells. It is concluded that the lethal effects of the hydroxamates are restricted to cells committed to DNA synthesis. Other cells in proliferating tissues escape damage during the limited time of circulation of inhibitory concentrations; this accounts for the prompt repair of tissue defects.

¹ Aided by Grants CA-03192 and CA-08748 from the National Cancer Institute, USPHS.

² Visiting Investigator, Chester Beatty Research Institute, London, September, 1965-July, 1966. during tenure of an Alfred P. Sloan Award in Cancer Research.

Received 6/15/66. Accepted 7/21/66.

This article has been cited by other articles:

				S. Bihorel, G. Camenisch, G. Gross, M. Lemaire, and J.-M. Scherrmann Influence of Hydroxyurea On Imatinib Mesylate (Gleevec) Transport at the Mouse Blood-Brain Barrier Drug Metab. Dispos., December 1, 2006; 34(12): 1945 - 1949. [Abstract] [Full Text] [PDF]

				S. K. Nilsson, M. S. Dooner, and P. J. Quesenberry Synchronized Cell-Cycle Induction of Engrafting Long-Term Repopulating Stem Cells Blood, December 1, 1997; 90(11): 4646 - 4650. [Abstract] [Full Text] [PDF]