Diet, Nutrition and Cancer: A Critical Evaluation

Volume II

Bandaru S. Reddy

• Publisher: CRC Press
• Year: 2018
• Print ISBN:
  9781315892283
• eBook ISBN:
  9781351088282
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

These two volumes bring together a wide variety of studies concerning the role nutrition plays in the etiology of various types of cancer, namely, cancer of the esophagus, upper alimentary tract, pancreas, liver, colon, breast, and prostate. The purpose of each chapter is to provide a critical interpretive review of the area, to identify gaps and inconsistencies in present knowledge, and to suggest new areas for future research.

Chapter 1

Retinoids and Mammary Gland Tumorigenesis: A Critique

Clifford W. Welsch, Maija H. Zile and Malford E. Cullum

TABLE OF CONTENTS

• I. Introduction
• II. Retinoids and Mammary Gland Tumorigenesis
  • A. Rats
  • B. Mice
  • C. Humans
  • D. Synopsis
• III. Mechanism by Which Retinoids May Influence Mammary Gland Tumorigenesis
  • A. Inhibition of Mammary Tumorigenesis by Retinoids: At the Initiation or Promotional Level?
  • B. Mechanisms
    • 1. Initiation Stage
      • a. Modifications of Carcinogen Metabolism
      • b. Modification of Cell Division
    • 2. Promotion Stage
      • a. Retinoid-Binding Proteins
      • b. Membrane Alterations
      • c. Modification of Cell Division
        • i. Inhibition of the Action of Mitogenic Peptides
        • ii. Induction of Differentiation: a cAMP Mediated Event?
      • d. Immune Stimulation
• IV. Conclusions
• Acknowledgments
• References

I. Introduction

In 1909 Stepp¹ first described a fat-soluble material which proved essential for life. Stepp carried out experiments on extracted “fat-free” diets and was able to show that the extracted food did not allow laboratory mice to survive unless an extract from egg yolk was added to the diet. Additional animal sources of the fat-soluble material were subsequently found in butter-fat and cod liver oil. In 1920, Drummond² suggested that the fat-soluble material should be called vitamin A. In 1931, Karrer et al.³ obtained vitamin A preparations of high purity and activity from fish liver oils and proposed the correct structural formula for vitamin A. By 1942, Baxter and Robeson⁴ succeeded in crystalizing pure vitamin A and several of its esters. The synthesis of crystalline vitamin A was first described by Isler et al.⁵ in 1947.

The term vitamin A is now used when reference is made to the biological activity of a number of vitamin A active substances. The three most common vitamin A active substances are retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinoic acid (vitamin A acid). All three compounds contain as common structural units a trimethylcyclohexenyl group and an all-trans polyene chain with four double bonds. Collectively, natural vitamin A compounds are important in general growth, growth and differentiation of epithelial tissues, visual function, and reproduction.

A relationship between vitamin A and cancer was suggested by Wolback and Howe,⁶ who in 1925 first described vitamin A deficiency in detail. In this early study, they also pointed out the similarity between vitamin A deficiency-induced metaplastic lesions in the epithelium of GI, respiratory, and urogenital tracts. In certain organs, these changes are regarded as a first step in neoplastic transformation. One year later, Fujimaki⁷ reported development of carcinomas in the stomach of laboratory rats which were fed a vitamin A-deficient diet. These early observations have led to testing of the concept that vitamin A compounds could be used in the prevention of tumorigenesis. In the late 1960s and early 70s a number of laboratories showed that induction of benign and malignant epithelial tumors in laboratory animals could be retarded or prevented by treatment of animals with relatively high doses of a variety of retinoids. To date, the chemopreventive effect by pharmacological doses of retinoids has been demonstrated in a variety of experimental tumor models and organ sites. Carcinogen-induced tumorigenesis in the bladder,⁸ cervix,⁹ vagina,⁹ colon,¹⁰ integument,¹¹ forestomach,⁹ tracheo-bronchi,¹² pancreas,¹³ liver,¹⁴ and mammary glands¹⁵ have been suppressed by feeding high levels of the vitamin.

The purpose of this communication is to review the relationship between retinoids and mammary gland tumorigenesis in rats, mice, and humans and to examine mechanism(s) by which retinoids might influence this neoplastic process. For those interested in the relationship between dietary vitamin A and tumorigenesis at organ sites other than the mammae, a number of reviews are available.^{16, 17, 18, 19, 20 and 21}

II. Retinoids and Mammary Gland Tumorigenesis

A. Rats

The first direct evidence of a significant inhibitory effect of high levels of dietary retinoids on the development of mammary tumors in experimental animals was reported by Moon et al.¹⁵ in 1976. Female Sprague-Dawley rats were intubated with a single dose of 7,12-dimethylbenzanthracene (DMBA) and 7 days later fed a standard laboratory chow containing retinyl acetate. Daily consumption of retinyl acetate was adjusted to either 1.0 or 2.5 mg/rat. The incidence of carcinomatous and benign mammary tumors 7 months after carcinogen treatment was significantly reduced in animals fed the natural retinoid. This study has been repeatedly confirmed in many laboratories using a variety of mammary gland carcinogens, i.e., DMBA, N-methyl-N-nitrosourea (MNU) and benzopyrene (BP), and dietary retinoids, i.e., retinyl acetate, retinyl methyl ether, 13-cis-retinoic acid and N-(4-hydroxyphenyl)retinamide (4-HPR) (Table 1).^{22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 and 34}

Table 1
INHIBITION OF CHEMICAL CARCINOGENESIS OF THE RAT MAMMARY GLAND BY DIETARY RETINOIDS^a

McCormick et al.²² initiated a series of studies to determine whether mammary tumorigenesis could be suppressed in DMBA-treated female rats when retinyl acetate feeding was limited to specific time periods during this neoplastic process. Feeding retinyl acetate at −2 to +1 weeks, + 1 to +30 weeks, +1 to +12 weeks, +12 to +30 weeks, and −2 to +30 weeks, where time 0 was the day of DMBA administration, resulted in a striking difference in tumorigenesis between these groups; 30 weeks after DMBA treatment mammary carcinoma incidence was significantly reduced in all groups but one (+1 to +12 weeks) when compared with placebo-fed controls. The greatest decrease in mammary tumor incidence was seen in the longest treatment group (− 2 to +30 weeks) but a nearly equal reduction was seen in the group receiving a short retinyl acetate exposure (− 2 to +1 weeks). In the +1 to +12 week group, the inhibition of tumor development was temporary; tumor incidence returned to that observed in placebo-fed control rats by 30 weeks postcarcinogen treatment. Nearly identical results were obtained in a subsequent study using a different carcinogen (BP).³⁴ However, when retinyl acetate feeding is delayed until 6 months after carcinogen treatment, the effectiveness of the retinoid may be reduced or absent.³⁵

In all of the cited studies in Table 1, large amounts of dietary retinoids (0.6 to 2.0 mM) were used for successful chemoprevention of rat mammary gland carcinogenesis. Dietary retinyl acetate levels as low as 0.2 mM is not, however, effective in the chemoprevention of rat mammary gland carcinogenesis.²⁵ This level of retinyl acetate (0.2 mM) still provides ≃20 times the daily requirement (IU) of vitamin A! Thus a narrow and continuous high level of the retinoid is prerequisite for successful chemoprevention of this neoplastic process. Retinyl acetate accumulates excessively in the liver, causing mild hepatic toxicity.³³ Whether or not retinyl acetate-induced hepatic toxicity affects this neoplastic process remains to be determined. Despite the mild hepatic toxicity, rats fed dietary levels of retinyl acetate up to 1.0 mM have normal body weight gains, normal estrous cycles, and in general appear as healthy as placebo-fed control animals. Certain synthetic retinoids (e.g., 4-HPR) do not accumulate excessively in the liver; therefore little or no hepatic toxicity is observed in these animals.³³ Thus, retinoid-induced prophylaxis of rat mammary gland carcinogenesis can be observed in animals without concurrent hepatic toxicity.

Table 2
ENHANCEMENT OF THE INHIBITORY ACTION OF DIETARY RETINOIDS ON RAT MAMMARY GLAND CARCINOGENESIS BY OTHER BIOLOGICAL RESPONSE MODIFERS

Recent studies have demonstrated that the chemopreventive activities of retinoids in rat mammary gland carcinogenesis can be significantly enhanced by other biological response modifiers, i.e., hormone antagonism, immune stimulation, and the administration of pharmacological levels of selenium (Table 2). In comparing the effectiveness of retinoid feeding, selenium treatment, and hormone antagonism in the prophylaxes of rat mammary gland carcinogenesis, it is clear that hormone antagonism is superior to retinoid feeding.^25,36 Retinoid feeding, on the other hand, appears to be slightly superior to selenium treatment.^28,30 Clearly, the effectiveness of retinoid feeding can be enhanced by either selenium treatment or hormone antagonism. Immune stimulation (cell particulate of mammary carcinoma plus Freund’s compl...

Table of contents

• Cover
• Title Page
• Copyright Page
• Preface
• The Editors
• Contributors
• Table of Contents
• Chapter 1 Retinoids and Mammary Gland Tumorigenesis: A Critique
• Chapter 2 Selenium and Murine Mammary Tumorigenesis
• Chapter 3 Chemoprevention of Cancer
• Chapter 4 Natural Inhibitors of Carcinogenesis: Fermented Milk Products
• Chapter 5 Epidemiologic Findings Relating Diet to Cancer of the Esophagus
• Chapter 6 Cancer Of The Esophagus: Epidemiological And Experimental Studies
• Chapter 7 Alcohol, Nutrition, and Cancer
• Chapter 8 Mutagens and Carcinogens in Food
• Chapter 9 Formation and Occurrence of Nitrosamines in Food
• Chapter 10 Diet, Nutrition, and Cancer: Directions for Research*
• Index