Carcinogenesis, Vol 18, 1007-1012, Copyright © 1997 by Oxford University Press
Z Zhu, AD Haegele and HJ Thompson
Caloric restriction has documented beneficial effects on numerous diseases
including cancer, yet the mechanism(s) that accounts for these wide ranging
benefits is unknown. Part of the difficulty in defining mechanisms has been
the long-term nature of experimental protocols in which these beneficial
effects have been observed and the inherent difficulty of investigating
mechanisms in such studies. The experiments reported were designed: (1) to
determine if caloric restriction would inhibit mammary carcinogenesis in a
model for this disease process that is 35 days in duration; (2) to
determine if progression from pre- malignant to malignant stages of mammary
carcinogenesis was affected by caloric restriction; and (3) to explore
whether the effects of caloric restriction were associated with changes in
adrenal function. Mammary carcinogenesis was induced in female
Sprague-Dawley rats by the i.p. administration of 1-methyl-1-nitrosourea
(50 mg/kg body weight) at 21 days of age. Rats were randomized to one of
four dietary treatment groups: ad libitum fed, or restriction of food
intake to 90, 80 or 60% of the ad libitum intake. Rats were palpated for
detection of mammary tumors and all mammary lesions excised at necropsy
were histologically classified. Twenty-four-hour collections of urine were
obtained at weekly intervals throughout the 35-day experiment. Urine was
assayed for corticosterone by direct radioimmunoassay. Caloric restriction
resulted in both a dose dependent prolongation of latency to palpable
carcinomas (P < 0.01) and a reduction in final incidence of mammary
cancer; the dose response was linear (P < 0.05). The percentage of pre-
malignant mammary lesions in a group increased with increasing degree of
caloric restriction, whereas the percentage of carcinomas decreased (P <
0.05). The level of cortical steroid increased linearly with increasing
caloric restriction (P < 0.01) an effect that was not attenuated over
time. Poisson regression analyses with the number of cancers per rat as the
dependent variable, level of caloric restriction as the independent
variable and urinary cortical steroid excretion as a co-variate were
performed. These analyses indicated that the variation in cancers per rat,
irrespective of the treatment group to which an animal was assigned, could
be accounted for by urinary cortical steroid excretion (P<0.05); i.e.
urinary cortical steroid excretion was an independent predictor of an
animal's carcinogenic response. The data reported in this study support the
use of a short term model to study the mechanism(s) by which caloric
restriction inhibits mammary carcinogenesis and point to both a stage in
the disease process, the conversion of pre-malignant to malignant cells,
and a target tissue (adrenal gland) and chemical species (adrenal cortical
steroid) that may be involved in mediating the protective effects of energy
restriction. These data indicate the feasibility of identifying a chemical
basis for the protective effect of caloric restriction that is independent
of energy restriction per se and this, in turn, indicates that it may be
possible to circumvent the practical problem of implementing a program of
chronic energy restriction in human populations, yet still achieve the
wide-ranging health benefits of such a program.
ARTICLES
Effect of caloric restriction on pre-malignant and malignant stages of mammary carcinogenesis
Division of Laboratory Research, AMC Cancer Research Center, Lakewood, CO 80214, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  O. P. Rogozina, M. J.L. Bonorden, J. P. Grande, and M. P. Cleary Serum Insulin-like Growth Factor-I and Mammary Tumor Development in Ad libitum-Fed, Chronic Calorie-Restricted, and Intermittent Calorie-Restricted MMTV-TGF-{alpha} Mice Cancer Prevention Research, August 1, 2009; 2(8): 712 - 719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zhu, W. Jiang, J. L. Sells, E. S. Neil, J. N. McGinley, and H. J. Thompson Effect of Nonmotorized Wheel Running on Mammary Carcinogenesis: Circulating Biomarkers, Cellular Processes, and Molecular Mechanisms in Rats Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 1920 - 1929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Jiang, Z. Zhu, and H. J. Thompson Dietary Energy Restriction Modulates the Activity of AMP-Activated Protein Kinase, Akt, and Mammalian Target of Rapamycin in Mammary Carcinomas, Mammary Gland, and Liver Cancer Res., July 1, 2008; 68(13): 5492 - 5499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhu, W. Jiang, J. N. McGinley, J. M. Price, B. Gao, and H. J. Thompson Effects of Dietary Energy Restriction on Gene Regulation in Mammary Epithelial Cells Cancer Res., December 15, 2007; 67(24): 12018 - 12025. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Moghaddam, M. Woodward, and R. Huxley Obesity and Risk of Colorectal Cancer: A Meta-analysis of 31 Studies with 70,000 Events Cancer Epidemiol. Biomarkers Prev., December 1, 2007; 16(12): 2533 - 2547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Cleary, X. Hu, M. E. Grossmann, S. C. Juneja, S. Dogan, J. P. Grande, and N. J. Maihle Prevention of Mammary Tumorigenesis by Intermittent Caloric Restriction: Does Caloric Intake During Refeeding Modulate the Response? Experimental Biology and Medicine, January 1, 2007; 232(1): 70 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Colbert, V. Mai, J. A. Tooze, S. N. Perkins, D. Berrigan, and S. D. Hursting Negative energy balance induced by voluntary wheel running inhibits polyp development in APCMin mice Carcinogenesis, October 1, 2006; 27(10): 2103 - 2107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhu, W. Jiang, J. N. McGinley, and H. J. Thompson 2-Deoxyglucose as an Energy Restriction Mimetic Agent: Effects on Mammary Carcinogenesis and on Mammary Tumor Cell Growth In vitro Cancer Res., August 1, 2005; 65(15): 7023 - 7030. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Krone and J. T. A. Ely Controlling Hyperglycemia as an Adjunct to Cancer Therapy Integr Cancer Ther, March 1, 2005; 4(1): 25 - 31. [Abstract] [PDF]
|
|
|
|
 |
|
 H. J. Thompson, Z. Zhu, and W. Jiang Weight Control and Breast Cancer Prevention: Are the Effects of Reduced Energy Intake Equivalent to Those of Increased Energy Expenditure? J. Nutr., December 1, 2004; 134(12): 3407S - 3411S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lee, M. Simpson, M. Nimmo, and Z. Xu Low zinc intake suppressed N-methyl-N-nitrosourea-induced mammary tumorigenesis in Sprague-Dawley rats Carcinogenesis, October 1, 2004; 25(10): 1879 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Thompson, J. N. McGinley, N. S. Spoelstra, W. Jiang, Z. Zhu, and P. Wolfe Effect of Dietary Energy Restriction on Vascular Density during Mammary Carcinogenesis Cancer Res., August 15, 2004; 64(16): 5643 - 5650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Jiang, Z. Zhu, J. N. McGinley, and H. J. Thompson Adrenalectomy Does Not Block the Inhibition of Mammary Carcinogenesis by Dietary Energy Restriction in Rats J. Nutr., May 1, 2004; 134(5): 1152 - 1156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Thompson, Z. Zhu, and W. Jiang Identification of the Apoptosis Activation Cascade Induced in Mammary Carcinomas by Energy Restriction Cancer Res., February 15, 2004; 64(4): 1541 - 1545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Platz, M. F. Leitzmann, D. S. Michaud, W. C. Willett, and E. Giovannucci Interrelation of Energy Intake, Body Size, and Physical Activity with Prostate Cancer in a Large Prospective Cohort Study Cancer Res., December 1, 2003; 63(23): 8542 - 8548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhu, W. Jiang, and H. J. Thompson Mechanisms by which energy restriction inhibits rat mammary carcinogenesis: in vivo effects of corticosterone on cell cycle machinery in mammary carcinomas Carcinogenesis, July 1, 2003; 24(7): 1225 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Jiang, Z. Zhu, and H. J. Thompson Effect of Energy Restriction on Cell Cycle Machinery in 1-Methyl-1-Nitrosourea-induced Mammary Carcinomas in Rats Cancer Res., March 15, 2003; 63(6): 1228 - 1234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Platz Energy Imbalance and Prostate Cancer J. Nutr., November 1, 2002; 132(11): 3471S - 3481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Jiang, Z. Zhu, N. Bhatia, R. Agarwal, and H. J. Thompson Mechanisms of Energy Restriction: Effects of Corticosterone on Cell Growth, Cell Cycle Machinery, and Apoptosis Cancer Res., September 15, 2002; 62(18): 5280 - 5287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Cleary, M. K. Jacobson, F. C. Phillips, S. C. Getzin, J. P. Grande, and N. J. Maihle Weight-Cycling Decreases Incidence and Increases Latency of Mammary Tumors to a Greater Extent Than Does Chronic Caloric Restriction in Mouse Mammary Tumor Virus- Transforming Growth Factor-{alpha} Female Mice Cancer Epidemiol. Biomarkers Prev., September 1, 2002; 11(9): 836 - 843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Thompson, Z. Zhu, and W. Jiang Protection against Cancer by Energy Restriction: All Experimental Approaches Are Not Equal J. Nutr., May 1, 2002; 132(5): 1047 - 1049. [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. McGinley, K. K. Knott, and H. J. Thompson Semi-automated Method of Quantifying Vasculature of 1-Methyl-1-nitrosourea-induced Rat Mammary Carcinomas Using Immunohistochemical Detection J. Histochem. Cytochem., February 1, 2002; 50(2): 213 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M.E Harvell, T. E. Strecker, B. Xie, K. L. Pennington, R. D. McComb, and J. D. Shull Dietary energy restriction inhibits estrogen-induced mammary, but not pituitary, tumorigenesis in the ACI rat Carcinogenesis, January 1, 2002; 23(1): 161 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhu, W. Jiang, and H. J. Thompson Effect of energy restriction on tissue size regulation during chemically induced mammary carcinogenesis Carcinogenesis, September 1, 1999; 20(9): 1721 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rodriguez-Burford, R. A. Lubet, I. Eto, M. M. Juliana, G. J. Kelloff, C. J. Grubbs, and V. E. Steele Effect of reduced body weight gain on the evaluation of chemopreventive agents in the methylnitrosourea-induced mammary cancer model Carcinogenesis, January 1, 1999; 20(1): 71 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. A. Leakey, J. E. Seng, C. R. Barnas, V. M. Baker, and R. W. Hart A Mechanistic Basis for the Beneficial Effects of Caloric Restriction On Longevity and Disease: Consequences for the Interpretation of Rodent Toxicity Studies International Journal of Toxicology, January 1, 1998; 17(2_suppl): 5 - 56. [Abstract] [PDF]
|
|