Day/night CR slows tumors in jet lag mice

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Hi All,

How does the timing at which meals are eaten affect hosts and their cancer

cells?

This question may have been examined in a new study. CR for a part of the day,

or

intermittent fasting, generally results in loss of body weight and consumption

of

fewer calories. However, these seemed not to occur in this study.

See the pdf-available below paper. The references at the end of the text

appeared

to be relevant relative to the penultimate paragraph.

son AJ, Straume M, Block GD, Menaker M.

Daily timed meals dissociate circadian rhythms in hepatoma and healthy host

liver.

Int J Cancer. 2005 Oct 17; [Epub ahead of print]

PMID: 16231323

Dividing cells, including human cancers, organize processes necessary for their

duplication according to circadian time. Recent evidence has shown that

disruption

of central regulation of circadian rhythms can increase the rate at which a

variety

of cancers develop in rodents. To study circadian rhythms in liver tumors, we

have

chemically induced hepatocellular carcinoma in transgenic rats bearing a

luciferase

reporter gene attached to the promoter of a core circadian clock gene (Period

1). We

explanted normal liver cells and hepatomas, placed them into short-term culture,

and

precisely measured their molecular clock function by recording light output.

Results

show that isolated hepatocellular carcinoma is capable of generating circadian

rhythms in vitro. Temporally restricting food availability to either day or

night

altered the phase of the rhythms in both healthy and malignant tissue. However,

the

hepatomas were much less sensitive to this signal resulting in markedly

different

phase relationships between host and tumor tissue as a function of mealtime.

These

data support the conclusion that hepatoma is differentially sensitive to

circadian

timing signals, although it maintains the circadian organization of the

nonmalignant

cells from which it arose. Because circadian clocks are known to modulate the

sensitivity of many therapeutic cytotoxic targets, controlling mealtiming might

be

used to increase the efficacy of treatment. Specifically, meal and treatment

schedules could be designed that take advantage of coincident times of greatest

tumor sensitivity and lowest sensitivity of host tissue to damage.

.... Wu, Filipski and colleagues recently demonstrated that daytime food

restriction

can inhibit tumor development in mice inoculated with Glasgow

osteosarcoma.[19][24]

Nighttime food restriction also inhibited tumor progression, but to a much

lesser

extent. This finding helped to differentiate between 2 competing explanations

for

the long-reported effects of caloric restriction on cancer: reduced caloric

intake

per se (as reviewed in the work of Kritchevsky[41]) vs. time of feeding. The

authors

of the study suggested that both caloric restriction and the temporal

restriction of

food intake to the light-phase act to inhibit tumor growth. The mechanisms

responsible for these effects are unknown. However, our results suggest one

possible

mechanism for alterations of tumor development by daytime food restriction. In

day-fed rats, HCC peaked 3 hr later than healthy tissue, while in night-fed rats

the

tumors peaked 3 hr earlier. Some specific phase relationships between tumors and

host may promote tumor proliferation, and other phase relationships may support

host-mediated defense against the cancerous tissue. Although our study did not

address the rate of tumor development, future experiments will address this

hypothesis by combining feeding schedules with assessment of molecular rhythms

in

tumor and host tissue while tracking the rate of tumor development.

The goal of chronomodulated chemotherapy is to adjust the temporal pattern of

drug

delivery to improve the toxic-therapeutic ratio. Adjustment of drug dosage by

time-of-day may serve 2 independent purposes: (i) to reduce doses at circadian

times

when healthy tissue is most susceptible to drug-induced toxicity and (ii) to

increase doses during circadian times at which the tumor is most susceptible to

the

effects of the drug. Clinical control over phase and amplitude of circadian

rhythms

in peripheral organs and tumors has the potential to markedly improve outcomes

in

patients receiving chronotherapy. In this study, we have shown that timed-meals

exert phase control over both healthy host liver and cancer, and that meal

timing

alters the phase-relationship between tumor and host. It should be possible to

design feeding regimes that differentially affect host and tumor rhythms and

thereby

allow drug administration at circadian times that minimize toxic side-effects to

healthy tissue while maximizing therapeutic effects on the tumor.

.... 19 Filipski E, Innominato PF, Wu M, Li XM, Iacobelli S, Xian LJ, Levi F.

Effects of light and food schedules on liver and tumor molecular clocks in

mice.

J Natl Cancer Inst. 2005 Apr 6;97(7):507-17.

2005 May 18;97(10):780.

PMID: 15812076

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=15812076

The below may suggest an answer to the issue of caloric intakes and is from

the

available full-text.

" Because ad libitum– and meal-fed mice had similar weights when tumors were

injected, we believe that the tumor growth differences in these two groups were

not

related to food restriction but rather depended upon the expression patterns of

the

molecular clock and cell cycle genes. The restored tumor molecular clock exerted

a

modest yet effective negative control of tumor progression, despite the atypical

phase relations within the clock's core mechanisms. "

.... 24 Wu MW, Li XM, Xian LJ, Levi F.

Effects of meal timing on tumor progression in mice.

Life Sci. 2004 Jul 23;75(10):1181-93.

PMID: 15219806

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=15219806 & query_hl=15

Al Pater, PhD; email: old542000@...

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