Abstract
The relevance of chronopharmacology for improving tolerability and antitumor efficacy of the antimitotic drug vinorelbine was investigated in female B6D2F1 mice standardized with 12 h of light and 12 h of darkness. A single i.v. vinorelbine dose (26 mg/kg) was given to 279 mice at 7, 11, 19, or 23 hours after light onset (HALO). Bone marrow necrosis and leukopenia were nearly twice as large in the mice injected at 7 HALO as compared with those treated at 19 HALO (ANOVA: p < .001 and p = 0.004, respectively). The relevance of vinorelbine dosing time for antitumor efficacy was assessed in 672 P388 leukemia-bearing mice. Vinorelbine was injected as a single dose (20, 24, 26, or 30 mg/kg) or weekly (20, 24, 26, or 28 mg/kg/injection × 3) at one of six circadian times, 4 h apart. A significant correlation between single dose and median survival time was limited to vinorelbine administration at 19 or 23 HALO. An increase in the vinorelbine weekly dose shortened median survival time in the mice treated at 7 HALO (20 mg/kg: 29 days; 24 mg/kg: 17 days; and 26 mg/kg: 6 days) but significantly improved it in those treated at 19 HALO (20 mg/kg: 28.5 days; 24 mg/kg: 32 days; and 26 mg/kg: 36 days). The study demonstrates the circadian rhythm dependence of maximum tolerated dose and the need to deliver maximum tolerated dose at the least toxic time to achieve survival improvement through chronotherapy. This may be obtained with an evening administration of vinorelbine in cancer patients.
Footnotes
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Send reprint requests to: Francis Lévi, Laboratoire “Rythmes Biologiques et Chronothérapeutique,” Institut du Cancer et d’Immunogénétique, Hôpital Paul Brousse, 14 Avenue P.V. Couturier, 94800 Villejuif, France. E-mail:frlevi{at}club-internet.fr
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↵1 This work was supported in part by the Association Internationale pour la Recherche sur le Temps Biologique et la Chronothérapie (ARTBC), by the Institut du Cancer et d’Immunogénétique, Hôpital Paul Brousse, 94800 Villejuif, France, and by Laboratoires Pierre Fabre Oncologie, 92100 Boulogne, France. Presented in part at the 88th Annual Meeting of the American Association for Cancer Research, April 12–16, 1997, San Diego, CA.
- Abbreviations:
- HALO
- hours after light onset
- MST
- median survival time
- %ILS
- percentage of increase in life span
- Received June 23, 1998.
- Accepted November 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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