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A theoretical analysis of interval drug dosing for cell-cycle-phase- specific drugs. (English) Zbl 0746.92012
Summary: A formal method is provided for predicting the effect of treatment efficacy of cell-cycle-phase-specific drugs, such as the AIDS drug zidovudine (AZT) or the cancer drug cytosine arabinoside (ara-C). Our analysis shows that the elimination of somatic cells or viruses depends not only on the drug’s pharmacokinetic and pharmacodynamic properties, but also on the duration of the dosing interval per se and on the life- cycle parameters, that is, the duration of the drug-susceptible life phase, the duration of the whole life cycle, and the proliferation rate. The results support those of simplified models in showing that drug toxicity to the host may be minimized when the dosing interval is an integer multiple of the average cycle time of the host susceptible cells. This prediction has been verified in mice treated with AZT or ara-C.

92C45 Kinetics in biochemical problems (pharmacokinetics, enzyme kinetics, etc.)
92C50 Medical applications (general)
Full Text: DOI
[1] Agur, Z., A new method of reducing cytotoxicity of the anti-AIDS drug AZT, (), 59-61
[2] Agur, Z., Clinical trials of zidovudine in HIV infection, Lancet, 334, ii, 734, (1989)
[3] Z. Agur, Increasing half life of cycle-specific drugs can increase elimination time, 2nd Cyprus Conference on New Methods in Drug Research, Limassol, p. 26.
[4] Agur, Z.; Arnon, R.; Schechter, B., Reduction of cytotoxicity to normal tissues by new regimens of phase-specific drugs, Math. biosci., 92, 1-15, (1988) · Zbl 0655.92004
[5] Agur, Z.; Arnon, R.; Sandak, B.; Schechter, B., Zidovudine toxicity to murine bone marrow may be affected by the exact frequency of drug administration, Exp. hematol., 19, 364-368, (1991)
[6] Z. Agur, R. Arnon, and B. Schechter, The effect of the dosing interval on myelotoxicity and survival in mice treated by cytosine arabinoside (in press).
[7] Arnold, V., Ordinary differential equations, (1973), MIT Press Cambridge, Mass · Zbl 0296.34001
[8] Breiman, L., Probability, (1968), Addison-Wesley Reading, Mass
[9] Carter, S.K.; Bakowski, M.T.; Hellman, K., Chemotherapy of cancer, (1981), Wiley New York
[10] Fischl, M.A., A randomized controlled trial of a reduced daily dose of zidovudine in patients with acquired immunodeficiency syndrome, N. engl. J. med., 323, 15, 1009-1014, (1990)
[11] Folks, T.; Powell, D.M.; Lightfoote, M.M.; Benn, S.; Martin, M.A.; Fauci, A.S., Induction of HTLV-III/LAV from a nonvirus-producing T-cell line: implications for latency, Science, 231, 600-602, (1986)
[12] Furukawa, T.; Ikeda, H., Cinemicrography of human erythroblasts: direct measurement of generation time and delineation of their pedigree, Blood cells, 12, 531-539, (1987)
[13] Greene, W.C., The molecular biology of human immunodeficiency virus type 1 infection, N. engl. J. med., 324, 308-317, (1991)
[14] Haus, E.; Halberg, F.; Pauly, J.E.; Kühl, J.F.W.; Sothern, R.B.; Shiotsuka, R.N.; Hwang, D.S., Increases tolerance of leukemic mice to arabinosyl cytosine with schedule adjusted to Circadian system, Science, 177, 80-82, (1972)
[15] Hryniuk, W.; Bush, H., The importance of dose intensity in chemotherapy of metastic cancer, J. clin. oncol., 2, 1281-1288, (1984)
[16] Izumi, H.; Guigon, M.; Frindel, E., Pluripotent haemopoietic stem cell entry into DNA synthesis in vitro after stimulation by ara-C treatment in vivo, Cell tissue kinet., 19, 477-483, (1986)
[17] Kim, S., Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: evidence for differential gene expression, J. virol., 63, 9, 3708-3713, (1989)
[18] Strychmans, P.; Cronkite, E.P.; Fache, J.; Fliendner, T.M.; Ramos, J., Nature, 211, 717-720, (1966)
[19] Tannock, I., Cell kinetics and chemotherapy: a critical review, Cancer treatment rep., 62, 1117-1133, (1978)
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