Chronopharmacology of Anticancer Agents
Several strategies are aimed at increasing the selectivity of anticancer agents against cancer cells. Some are based on tumor cell biology: new drug development, resistance revertants, etc. Others are targeted at host cells: development of analogs with le
- PDF / 4,013,941 Bytes
- 33 Pages / 439.37 x 666.142 pts Page_size
- 107 Downloads / 210 Views
Chronopharmacology of Anticancer Agents F. LEVI
A. Introduction Several strategies are aimed at increasing the selectivity of anticancer agents against cancer cells. Some are based on tumor cell biology: new drug development, resistance revertants, etc. Others are targeted at host cells: development of analogs with less toxicity than the parent drug, combinations of cytostatics without additive toxicities, scheduling and/or supportive care in order to increase chemotherapy tolerability, etc. (DE VITA et al. 1993). A doseefficacy relationship has been repeatedly established for cancer chemotherapy (HRYNIUK 1988). For this reason, the chronobiology of normal cells has constituted the main basis for attempting to improve the therapeutic index of cytostatic drugs. It was expected that an increase in drug doses, and therefore therapeutic efficacy, would result from an adaptation of drug delivery to circadian rhythms (chronotherapy). We will examine the several steps which have led to the validation of the clinical relevance of chronotherapy in medical oncology that was anticipated more than 20 years ago (HAUS et al. 1972; HALBERG et al. 1973). Only the circadian aspects will be considered.
B. Experimental Chronopharmacology I. Toxicity Rhythms Circadian dosing time influences the extent of toxicity of -30 anticancer drugs, including cytostatics and cytokines, in mice and rats (LEVI et al. 1988a, 1994a; MORMONT et al. 1989; PERPOINT et al. 1995). The methodology that was mostly used to demonstrate this phenomenon firstly consisted of the administration of the same drug dose to different groups of animals, each group corresponding to a different circadian stage. Six circadian stages, usually located 4 h apart, have commonly been used. Time has usually been expressed in hours after light onset (HALO). Nocturnally active mice or rats have mostly been synchronized for 13 weeks with an alternation of 12 h light (L) and 12 h darkness (D) (LD 12:12). A 3-week span appears a safe period for biological rhythms to adjust to a synchronization regimen differing by 8 h or more from the previous one. Other photoperiodic schemes have occasionally been used: natural LD, which varies according to the season and latitude; artificial LD 8:16 (so-called P. H. Redfern et al. (eds.), Physiology and Pharmacology of Biological Rhythms © Springer-Verlag Berlin Heidelberg 1997
300
F. LEVI
winter photoperiod); or LD 16:8 (so-called summer photoperiod). Autonomous chronobiologic facilities have largely improved the feasibility of chronopharmacologic experiments since they allow for any endogenous circadian stage to be explored at any desired local time. For all these drugs, survival rate varies by 50% or more according to circadian dosing time of a potentially lethal dose. Such large differences are observed irrespective of injection route intravenous or intraperitoneal - or number of injections - single or repeated (Figs. 1,2). Pirarubicin, an anthracycline compound, mostly exerts myelosuppressive effects, which are lowest following dosing i
Data Loading...
