J. Bradley Aust, M.D., Ph.D. Emeritus 1960 3/17/2010 Charles T. Beer, D.Phil. Emeritus 1973 6/15/2010 Charles W. Boone, M.D., Ph.D. Emeritus 1976 5/14/2010 Michael J. Brennan, M.D. Emeritus 1958 9/22/2010 Ashley M. Brown, D.D.S. Emeritus 1974 5/27/2010 Raymond R. Brown, Ph.D. Emeritus 1956 6/23/2010 Richard A. Consigli, Ph.D. Emeritus 1976 12/10/2010 Margarida M. Dederick, M.D. Emeritus 1963 11/21/2010 Merrill J. Egorin, M.D. Active 1978 8/7/2010 Harry V. Gelboin, Ph.D. Emeritus 1963 4/13/2010 Alan M. Gewirtz, M.D. Active 1995 11/17/2010 David A. Goldthwait, M.D. Emeritus 1975 4/12/2010 Bernard Grad, Ph.D. Emeritus 1950 12/27/2010 Samuel Gross, M.D. Emeritus 1981 10/3/2010 Petre N. Grozea, M.D. Emeritus 1973 3/26/2010 Paul Hochstein, Ph.D. Emeritus 1962 6/12/2010 Karen A. Johnson, M.D., Ph.D. Active 2001 8/16/2010 Fred F. Kadlubar, Ph.D. Active 1978 12/4/2010 Karl Karrer, M.D. Emeritus 1967 8/27/2010 Paul S. Lavik, Ph.D. Emeritus 1958 10/20/2010 Elizabeth H. Leduc, Ph.D. Emeritus 1959 1/30/2010 Leon L. Miller, Ph.D. Emeritus 1958 9/3/2010 Gerald C. Mueller, M.D., Ph.D. Emeritus 1948 11/7/2010 Gregory R. Mundy, M.D. Active 2002 2/25/2010 Leo Orris, M.D. Emeritus 1963 6/16/2010 William W. Payne, Sc.D. Emeritus 1962 12/20/2010 Aaron R. Rausen, M.D. Emeritus 1975 7/7/2010 Allen F. Reid, M.D., Ph.D. Emeritus 1951 7/30/2010 Benjamin A. Rubin, Ph.D. Emeritus 1956 3/8/2010 Robert J. Rutman, Ph.D Emeritus 1962 9/20/2010 Jessie A. Satia, Ph.D. Active 1999 2/4/2010 Kathy Schiffman, B.A. Affiliate 2002 5/15/2010 Jennie B. Shatton, M.S. Emeritus 1969 9/21/2010 Hisashi Shinozuka, M.D., Ph.D. Emeritus 1972 9/20/2010 Ian C. Summerhayes, Ph.D. Active 1991 7/20/2010 Richard D. Williams, M.D. Active 1981 5/28/2010

Shue, Jerry L. OD, BS1; Sothern, Robert B. PhD2; Kanabrocki, Eugene L. PhD3; Bremner, William F. MD, PhD3; Nemchausky, Bernard M. MD3; Vesely, David L. MD, PhD4; Feuers, Ritchie J. PhD5; Scheving, Lawrence E. PhD6; Olwin, John H. MD7 Author Information

Chemotherapy is curative in selected widespread malignancies, including childhood leukemia, testicular cancer, and malignant lymphomas. However, the most commonly occurring malignant diseases, including lung, gastrointestinal, and renal cell cancer, respond poorly or not at all even to aggressive cytotoxic therapy. The treatment goal for these metastatic tumors is palliation, not cure. As chemotherapy may not even prolong survival significantly, its application needs to be critically reviewed as to how it affects the patient’s quality of life.

This paper is based on a presentation given as the opening address before a symposium on Chronobiology held during the 11th Collegium Internationale Neuro-psychopharmacologicum Congress in Vienna, Austria, 9-14 July 1978. The author discusses the ubiquitous nature of rhythms, current terminology, the different frequencies found, and the current methods used for analyzing time-series data. Rhythms having frequencies of about a day, the circadian, are emphasized throughout the paper; the different properties of circadian rhythms are described; and examples are given of a number of diverse circadian rhythms in rodent and man. Finally, some potential applications of chronobiological principles to medicine are suggested.

When cyclophosphamide and 1-beta-D-arabinofuranosylcytosine were administered to mice previously given injections of L1210 leukemia cells, the combination was more effective than either drug given alone. The effectiveness of the 2 drugs in combination was strongly influenced by the stage of the circadian system at which the drugs were administered. With the use of a chronobiological (sinusoidal) approach, in comparison with one or two conventional treatment schedules, it was possible to demonstrate an overall lower toxicity as monitored by death or weight loss. In general, mean survival times and cures (when obtained) were circadian stage dependent; for example, in 1 study the cure rate was 94% in mice treated at 1 circadian stage, but only 44% in those treated at another stage. It cannot be overemphasized, however, that just as the "right" timing can enhance (with statistical significance) both the tolerance to chemotherapeutic agents and the rate of cure in leukemic mice, so can the "wrongly" timed (wrongly placed) ara-C sinusoid or "wrongly" timed cyclophosphamide enhance toxicity and host death rate.

Oscillation is a fundamental property of all animal and plant life: it also characterizes all levels of organization from the molecular to that of the whole organism. This chapter focuses on the circadian rhythms or those with a frequency of about a day. It should be kept in mind that rhythms of higher (ultradian) or lower (infradian) frequency may be superimposed on the circadian frequency. The frequency spectrum of rhythms is broad, ranging from fractions of a minute to days or months or even a year. The chapter describes some generalizations about mammalian chronobiology, then introduces several descriptive terms and cites examples of biological rhythms. The attention then gets focused on chronopharmacological implications. Because the biological system is rhythmically changing, it follows that the organism is biochemically a different entity at different circadian phases; therefore it reacts differently to an identical stimulus at different times. Researchers have been exploring rhythms in various organs in both the tumor-bearing and normal animal. High-amplitude circadian rhythms have been reported for the DNA synthesis in liver, bone marrow, gut, thymus, and spleen of normal rodents; the presence of a tumor may dramatically alter the rhythm.