Hydroxyurea (HU) was administered by continuous i.v. infusion to L1210 tumor-bearing mice (105 cells, Day 0) beginning on Day 5. Doses of 1, 12, 48, 96, and 192 mg/kg/hr were infused for periods of 1 to 48 hr. Sequential changes in cell count, [3H]thymidine labeling index, grain count, DNA content distribution (determined by flow microfluorometry), and survival times were determined. The two lowest doses (1 and 12 mg/kg/hr) induced little cytotoxicity or progression delay at the G1-S boundary, and survival times were not significantly different from the control value. The effects of the higher doses of HU were dose dependent. HU (48 mg/kg/hr) effectively synchronized cells in S phase. After 24 hr, little cytotoxicity occurred, and once the infusion was ended the synchronized cells continued to progress into G2 and mitosis at a rate similar to that of unperturbed cells. Detectable synchrony was maintained through one generation. Cytotoxicity increased with infusion times longer than 24 hr. The increase in survival times with this dose of HU was equivalent to the duration of the infusion. HU (96 and 192 mg/kg/hr) was markedly cytotoxic resulting in 95% cell loss by 48 hr. The grain count decreased markedly by 4 hr after both doses, and the flow microfluorometry histograms demonstrated progression delay within 4 hr. Maximum increases in life span of 4.7 days (56%) and 5.6 days (68%), respectively, were obtained after 32-hr infusions. Toxicity occurred with infusions longer than 32 hr. These data indicate that the effects of HU in vivo are dependent on the dosage and duration of the infusion. High infusion doses are required to kill cells in vivo. Lower, noncytotoxic dose levels may effectively be used to synchronize cells in S phase.

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This study was supported by Grant CA 18837 from the National Cancer Institute and Grant CH-54 from the American Cancer Society.

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