TIME DEPENDENCY OF HEMATOPOIETIC GROWTH-FACTOR COUPLED TO CHRONOTOXICITY OF CARBOPLATIN

A growing body of data suggests that cancer therapy may be improved an d toxicity reduced by administration of antineoplastic agents and cyto kines at carefully selected times of the day. The time-dependent effec ts of each of the drugs have been documented, but not their mutual tim e dependencies. In the present studies we sought to determine the best time for granulocyte colony-stimulating factor (G-CSF) administration after carboplatin treatment. Carboplatin was injected in different gr oups of ICR mice at four different circadian stages for 5 consecutive days. Mice were synchronized with an alternation of 12 h of light (fro m 6:00 a.m. to 6:00 p.m.) and 12 h of darkness. After the last injecti on, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Bone marrow toxicity was estimated with the mea n 24-h WBC count. The most severe leukopenia occurred in the group inj ected at 3:00 p.m. -9 h after light onset. The second set of experimen ts evaluated the time-dependent effect of G-CSF when singly injected o r given after carboplatin injections for 5 days only at 3:00 p.m. G-CS F was injected into various groups on days 8 and 9 at the same four di fferent circadian stages. On the 10th day after the first injection, p eripheral WBCs of three mice from each group were counted every 4 h ov er a 24-h period. Time-dependent effects were observed when G-CSF was injected as a single agent. When G-CSF was given at various times to t he group with the most severe carboplatin-induced leukopenia, peripher al WBC count recovery was monitored at all injection times; it reached its highest level (exceeding even that of the control) when G-CSF was injected at 3:00 a.m. Dosing times of both chemotherapy and growth fa ctor are relevant for optimization of carboplatin's hematologic tolera bility.