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The cytokinetic and cytotoxic effects of ICRF-159 and ICRF-187 in vitro and ICRF-187 in human bone marrow in vivo

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Summary

The cytotoxic and cytokinetic effects of ICRF-159 and its d-enantiomer ICRF-187 have been examined in vitro. The effects of both agents were identical. Cytotoxicity is dependent on both the drug concentration and the duration of drug exposure. Drug exposure for twice the cell cycle time is necessary for maximum effect. Cytotoxicity is also dependent upon the rate of cell proliferation. A rapidly growing cell population is more sensitive to brief drug exposure than a slowly growing population.

The cytokinetic effects were studied using flow cytometry, determination of [3H]-thymidine incorporation and mitotic index. ICRF-159/187 appears to act only during the G2 phase of the cell cycle. There is no detectable delay in cell passage through the G1/S boundary or in transit through S phase. Inhibition of DNA synthesis occurs only after the G2 block prevents subsequent entry of cells in S phase. A fraction of the cells, depending upon drug concentration, undergo further DNA synthesis without cell division, resulting in a tetrapoid cell population.

The cytokinetic effects were determined in the bone marrow of patients receiving ICRF-187. All dose-rates produced G2/M accumulation in the marrow with depletion of S phase cells. One patient was given a single injection of 1.0 gm/M2. G2/M accumulation was observed 24 h after treatment, with recovery to a pretreatment DNA cycle distribution 24 h later.

These studies suggest that a continuous drug infusion, or intermittent infusions timed to allow the normal cell population to recover, may produce superior clinical activity with this agent. A Phase I study of such an intermittent schedule is indicated.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan, USA

    Richard H. Wheeler M.D., Daniel J. Clauw & Ronald B. Natale

  2. Veterans Administration Medical Center, Ann Arbor, Michigan, USA

    Ronald B. Natale

  3. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA

    Raymond W. Ruddon

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  1. Richard H. Wheeler M.D.
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  2. Daniel J. Clauw
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  3. Ronald B. Natale
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  4. Raymond W. Ruddon
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Wheeler, R.H., Clauw, D.J., Natale, R.B. et al. The cytokinetic and cytotoxic effects of ICRF-159 and ICRF-187 in vitro and ICRF-187 in human bone marrow in vivo . Invest New Drugs 1, 283–295 (1983). https://doi.org/10.1007/BF00177411

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