Increased Tolerance of Leukemic Mice to Arabinosyl Cytosine with Schedule Adjusted to Circadian System

Haus, Erhard; Halberg, Franz; Scheving, Lawrence E.; Pauly, John E.; Cardoso, Sílvia Almeida; Kühl, Jüurgen F. W.; Sothern, Robert B.; Shiotsuka, Ronald N.; Hwang, Dar Shong

doi:10.1126/science.177.4043.80

Cited by 149 publications

(47 citation statements)

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“…13 This initial observation was later extended to testing the effect of timed administration of over 30 anticancer agents in mice and rats. 14 For most of them, the differences in toxicity ranged from 2-to 8-fold depending upon the time of their administration.…”

Section: Chronotherapy-beneficial But Inconvenient For Practical Applmentioning

confidence: 99%

Circadian Clock Genes as Modulators of Sensitivity to Genotoxic Stress

Antoch¹,

Kondratov²,

Takahashi³

2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=1792 KEY WORDSCircadian, CLOCK, BMAL1, transcription, anticancer therapy Review Circadian Clock Genes as Modulators of Sensitivity to Genotoxic Stress ABSTRACTA broad variety of organisms display circadian rhythms (i.e., oscillations with 24-hr periodicities) in many aspects of their behavior, physiology and metabolism. These rhythms are under genetic control and are generated endogenously at the cellular level. In mammals, the core molecular mechanism of the oscillator consists of two transcriptional activators, CLOCK and BMAL1, and their transcriptional targets, CRYPTOCHROMES (CRYS) and PERIODS (PERS). The CRY and PER proteins function as negative regulators of CLOCK/BMAL1 activity, thus forming the major circadian autoregulatory feedback loop. It is believed that the circadian clock system regulates daily variations in output physiology and metabolism through periodic activation/repression of the set of clock-controlled genes that are involved in various metabolic pathways. Importantly, circadian-controlled pathways include those that determine in vivo responses to genotoxic stress. By using circadian mutant mice deficient in different components of the molecular clock system, we have established genetic models that correlate with the two opposite extremes of circadian cycle as reflected by the activity of the CLOCK/BMAL1 transactivation complex.Comparison of the in vivo responses of these mutants to the chemotherapeutic drug, cyclophosphamide (CY), has established a direct correlation between drug toxicity and the functional status of the CLOCK/BMAL1 transcriptional complex. We have also demonstrated that CLOCK/BMAL1 modulates sensitivity to drug-induced toxicity by controlling B cell responses to active CY metabolites. These results suggest that the sensitivity of cells to genotoxic stress induced by anticancer therapy may be modulated by CLOCK/BMAL1 transcriptional activity. Further elucidation of the molecular mechanisms of circadian control as well as identification of specific pharmacological modulators of CLOCK/BMAL1 activity are likely to lead to the development of new anti-cancer treatment schedules with increased therapeutic index and reduced morbidity. ANTICANCER THERAPY-A DOUBLE-EDGED SWORDTwo major types of anticancer therapy-chemotherapy and radiation-were introduced into the clinic several decades ago and have demonstrated significant success in treating a variety of tumors. However, both types of anticancer therapy are compromised by accompanying nonspecific damage to normal tissues that often results in debilitating side effects. Well-known examples of such complications include the hematopoietic syndrome (induced by radiation and some DNA-damaging chemotherapeutic drugs, such as cyclophosphamide), direct neurotoxicity (induced by vinca alkaloids), damage to the oral mucosa, kidney and bladder, radiation-induced damage to intestinal epithelia, and many others. All of these si...

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Section: Chronotherapy-beneficial But Inconvenient For Practical Applmentioning

confidence: 99%

Circadian Clock Genes as Modulators of Sensitivity to Genotoxic Stress

Antoch¹,

Kondratov²,

Takahashi³

2005

Cell Cycle

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“…Observations made Ͼ30 years ago demonstrated that the circadian pattern of arabinosyl cytosine administration determined both its toxicity and antitumor activity (8). More than 30 different anticancer drugs tested in mice and rats exhibit strong time-of-administration effects on drug-induced toxicity (9).…”

mentioning

confidence: 99%

Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex

Gorbacheva

Kondratov

Zhang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

236

202

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The circadian clock controls many aspects of mammalian physiology, including responses to cancer therapy. We find that wild-type and circadian mutant mice demonstrate striking differences in their response to the anticancer drug cyclophosphamide (CY). While the sensitivity of wild-type mice varies greatly, depending on the time of drug administration, Clock mutant and Bmal1 knockout mice are highly sensitive to treatment at all times tested. On the contrary, mice with loss-of-function mutations in Cryptochrome (Cry1 ؊/؊ Cry2 ؊/؊ double knockouts) were more resistant to CY compared with their wild-type littermates. Thus, both time-of-day and allelic-dependent variations in response to chemotherapy correlate with the functional status of the circadian CLOCK/BMAL1 transactivation complex. Pharmacokinetic analysis of plasma concentration of different CY metabolites shows that, in contrast to the traditional view, circadian variations in drug sensitivity cannot be attributed to the changes in the rates of CY metabolic activation and͞or detoxification. At the same time, mice of different circadian genotypes demonstrate significant differences in B cell responses to toxic CY metabolites: B cell survival͞recovery rate was directly correlated with the in vivo drug sensitivity. Based on these results, we propose that the CLOCK͞BMAL1 transcriptional complex affects the lethality of chemotherapeutic agents by modulating the survival of the target cells necessary for the viability of the organism.chemotherapy ͉ circadian clock ͉ drug response A broad range of organisms from bacteria to animals display circadian oscillations in metabolism, cell proliferation, physiology, and behavior. Circadian rhythms are generated by an intracellular clock mechanism that involves a network of transcriptional feedback loops that drive rhythmic RNA and protein expression of key clock components (reviewed in refs.

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“…It is well documented that the susceptibility to cancer chemotherapy shows circadian variations in laboratory animals (Haus et al, 1972;Scheving et al, 1976;Levi et al, 1982). In addition to reduced mortality due to acute toxicity, it has also been shown that an increase in tumour effect or cure rate can be obtained by timing the therapy to periods with less susceptibility of normal cells (Haus et al, 1972;Kuhl et al, 1974;Scheving et al, 1980a;Scheving et al, 1980b;Sothern et al, 1989;Roemeling & Hrushesky, 1990).…”

mentioning

confidence: 99%