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The Combined Effect of Hydroxyurea and X-rays on Chinese Hamster Cells in Vitro¹

Division of Biological and Medical Research, Argonne National Laboratory, Argonne, Illinois 60439

Hydroxyurea inhibits DNA synthesis in Chinese hamster cells and is selectively toxic for cells actually in DNA synthesis (i.e., in S phase) at the time of exposure to the drug. Synchronized cells in G₁ inhibited from entering S by hydroxyurea show a complex response to X-radiation. Cells become steadily more sensitive for a period of about 4 hr and then recover about a normal G₁ sensitivity in approximately a further 4 hr. They never achieve the high survival level normally found for uninhibited cells in late S, but they will reach this level quite rapidly if the hydroxyurea is removed prior to exposure. The sensitization is, therefore, completely reversible. Hydroxyurea has no effect if present only during exposure at room temperature. Additional sensitization is obtained if the drug is present after exposure which increases for a period of about 4 hr. This postirradiation sensitization is independent of the time in the cycle at which irradiation takes place.

These results with synchronized populations enable the effects of hydroxyurea on asynchronous populations to be predicted. The most sensitive condition occurs when irradiation is given about 4 hr after the administration of hydroxyurea and the drug is kept on subsequently.

The results indicate that hydroxyurea in combination with X-rays can be a most effective toxic agent for Chinese hamster cells. If these results are applicable to in vivo situations, combination therapy with hydroxyurea given systemically and X-rays delivered locally to tumors may be most effective. However, in view of some of the problems in tumor control that cannot be evaluated in vitro, experiments with suitable animal tumor systems are needed.

¹ This work was supported by the U. S. Atomic Energy Commission.

Received 5/29/67. Accepted 10/ 3/67.

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