Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

https://science.sciencemag.org/content/sci/275/5297/218.full.pdf

Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes

Chemoprevention of cancer is a means of cancer control in which the occurrence of this disease is prevented by administra tion of one or several chemical compounds. This Perspective deals with the areas in cancer control that this field addresses, the promise that it holds, and the problems that must be solved in order to realize its goals. The most desirable way of eliminating the impact of cancer in humans is by prevention. The first set of strategies for achieving this objective is to remove the causative agents. In some instances, as with cigarette smoking, it is possible to eliminate the etiological agent. However, in others it is not. The causes of most cancers in the human are not known. Under some circumstances, even when causative factors are known, neoplasia may have been initiated, and prevention now falls into the realm of suppressing the evolution of the neoplastic process. Individuals already exposed to carcinogens fall into this category as do individuals at high risk to cancer because of genetic factors. Finally, there are a considerable number of suspect carcinogens in the environment that have been identified by virtue of mutagenicity testing. Many of these mutagenic substances occur in food. The carcinogenic potential of these compounds for the human is not clear. If they do in fact play a role in the occurrence of cancer, it would be exceedingly difficult to remove them from the environment. Flavones in food are an example of a class of compounds that are mutagenic and that would be virtually impossible to remove because of their ubiqui tous distribution. Likewise, if exposure to oxygen radicals and epoxides poses a hazard, as has been suggested by some investigators, such exposures would be difficult to prevent. While removal of causative agents is the primary goal of cancer pre vention, for the foreseeable future it is likely to be incomplete. Accordingly, the development of a second line of prevention based on Chemoprevention assumes considerable importance. The human constituencies that would be the target for Chemoprevention vary. Two extremes are apparent, but in all likelihood a continuum exists between them. At one extreme are individuals at very high risk of developing cancer because of genetic predisposition or exposure to carcinogens. At the other end of the risk spectrum are individuals lacking any evidence of an increase in risk factors. The strategies for dealing with groups at varying risks differ. As the risk for developing cancer increases, the compounds likely to be most effective are those that sup press evolution of the neoplastic process. The permissible risk of toxicity from the chemopreventive agent also will increase. In contrast, when one considers chemopreventive agents to be directed at populations with no enhanced risk from cancer, protection against attack from compounds that are involved in the causation of cancer assumes a greater importance. For this

https://cancerres.aacrjournals.org/content/canres/45/1/1.full.pdf

Chemoprevention of Cancer

The three-dimensional structure of calmodulin has been determined crystallographically at 3.0 A resolution. The molecule consists of two globular lobes connected by a long exposed alpha-helix. Each lobe binds two calcium ions through helix-loop-helix domains similar to those of other calcium-binding proteins. The long helix between the lobes may be involved in interactions of calmodulin with drugs and various proteins.

Three-dimensional structure of calmodulin

It has been known for more than 50 years that retinoids, the family of molecules comprising both the natural and synthetic analogues of retinol, are potent agents for control of both cellular differentiation and cellular proliferation (70). In their original clas sic paper describing the cellular effects of vitamin A deficiency in the rat, Wolbach and Howe clearly noted that there were distinct effects on both differentiation and proliferation of epithelial cells. During vitamin A deficiency, it was found that proper differentia tion of stem cells into mature epithelial cells failed to occur and that abnormal cellular differentiation, characterized in particular by excessive accumulation of keratin, was a frequent event. Furthermore, it was noted that there was excessive cellular proliferation in many of the deficient epithelia. Although the conclusion that an adequate level of retinoid was necessary for control of normal cellular differentiation and proliferation was clearly stated in the original paper by Wolbach and Howe, a satisfactory explanation of the molecular mechanisms underlying these effects on both differentiation and proliferation still eludes us more than 50 years later. It was inevitable that the basic role of retinoids in control of cell differentiation and proliferation would eventually find practical application in the cancer field, and there have been great ad vances in this area, particularly for prevention of cancer. Many studies have shown that retinoids can suppress the process of carcinogenesis in vivo in experimental animals (for reviews, see Refs. 7, 33, 51, 54, 56, and 57), and these results are now the basis of current attempts to use retinoids for cancer prevention in humans. Furthermore, there is now an extensive literature on the ability of retinoids to suppress the development of the malignant phenotype in vitro (for reviews, see Refs. 6, 8, 30, and 31 ), and these studies corroborate the use of retinoids for cancer prevention. Finally, most recently, it has been shown that reti noids can exert effects on certain fully transformed, invasive, neoplastic cells, leading in certain instances to a suppression of proliferation (30) and in other instances to terminal differentiation of these cells, resulting in a more benign, nonneoplastic pheno type (10,11,60,62). Even though there are many types of tumor cells for which this is not the case (33, 52) (indeed, at present there are only a limited number of instances in which such profound effects of retinoids on differentiation and proliferation of invasive tumor cells have been shown), this finding neverthe less has highly significant implications for the problem of cancer treatment. It emphasizes that in many respects cancer is fun damentally a disease of abnormal cell differentiation (36,44), and it raises the possibility that even invasive disease may eventually be controlled by agents which control cell differentiation rather than kill cells. Since carcinogenesis is essentially a disorder of cell differentiation, the overall scientific problem of the role of retinoids in either differentiation or carcinogenesis is essentially

https://cancerres.aacrjournals.org/content/canres/43/7/3034.full.pdf

Role of retinoids in differentiation and carcinogenesis.

13-cis-Retinoic acid has been reported to be effective in treating oral leukoplakia. We randomly assigned 44 patients with this disease to receive 13-cis-retinoic acid (24 patients) or placebo (20), 1 to 2 mg per kilogram of body weight per day for three months, and followed them for six months. There were major decreases in the size of the lesions in 67 percent (16 patients) of those given the drug and in 10 percent (2 patients) of those given placebo (P = 0.0002); dysplasia was reversed in 54 percent (13 patients) of the drug group and in 10 percent (2 patients) of the placebo group (P = 0.01). The clinical response to the drug correlated with the histologic response in 56 percent (9 of 16) of the patients evaluated. Relapse occurred in 9 of 16 patients two to three months after treatment ended. The toxic effects of the drug were acceptable in all but two patients. Cheilitis, facial erythema, and dryness and peeling of the skin were common; conjunctivitis and hypertriglyceridemia also occurred. All adverse reactions could be reversed by reducing the dose or temporarily discontinuing the drug. We conclude that 13-cis-retinoic acid, even in short-term use, appears to be an effective treatment for oral leukoplakia and has an acceptable level of toxicity.

13-cis-retinoic acid in the treatment of oral leukoplakia.

The importance of retinoids for chemoprevention of cancer has received further emphasis with the finding that retinoids can suppress in vitro expression of the malignant phenotype, whether it be caused by chemical carcinogens, radiation, or viral transforming factors. Retinoids have been found to be potent inhibitors of the tumor-promoting effects of phorbol esters. Further advances in the chemistry of synthetic retinoids have led to the development of new agents that show less toxicity and better targeting to specific organ sites than natural retinoids. Synthetic retinoids have been particularly useful for prevention of bladder and breast cancer in experimental animals.

Chemoprevention of cancer with retinoids.

Agonist and Antagonist Properties of Calmodulin Fragments

Expression and characterization of recombinant human eosinophil-derived neurotoxin and eosinophil-derived neurotoxin-anti-transferrin receptor sFv.

Cytotoxic ribonuclease chimeras. Targeted tumoricidal activity in vitro and in vivo.

Purkinje cell toxicity is one of the characteristic features of the Gordon phenomenon, a syndrome manifested by ataxia, muscular rigidity, paralysis, and tremor that may lead to death (Gordon, 1933). Two members of the RNase superfamily found in humans, EDN (eosinophil- derived neurotoxin) and ECP (eosinophil cationic protein), cause the Gordon phenomenon when injected intraventricularly into guinea pigs or rabbits. We have found that another member of the RNase superfamily, an antitumor protein called onconase, isolated from Rana pipiens oocytes and early embryos, will also cause the Gordon phenomenon when injected into the cerebrospinal fluid of guinea pigs at a dose similar to that of EDN (LD50, 3–4 micrograms). Neurologic abnormalities of onconase- treated animals were indistinguishable from those of EDN-treated animals, and histology showed dramatic Purkinje cell loss in the brains of onconase-treated animals. The neurotoxic activity of onconase correlates with ribonuclease activity. Onconase modified by iodoacetic acid to eliminate 70% and 98% of the ribonuclease activity of the native enzyme displays a similar decrease in ability to cause the Gordon phenomenon. In contrast, the homologous bovine pancreatic RNase A injected intraventricularly at a dose 5000 times greater than the LD50 dose of EDN or onconase is not toxic and does not cause the Gordon phenomenon. A comparison of the RNase activities of EDN, onconase, and bovine pancreatic RNase A using three pancreatic RNA substrates demonstrates that onconase is orders of magnitude less active enzymatically than EDN and RNase A. Thus, another member of the RNase superfamily in addition to EDN and ECP can cause the Gordon phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)

https://www.jneurosci.org/content/jneuro/14/2/538.full.pdf

Dianne L. Newton

Papers

Chemoprevention of cancer with retinoids.

Agonist and Antagonist Properties of Calmodulin Fragments

Expression and characterization of recombinant human eosinophil-derived neurotoxin and eosinophil-derived neurotoxin-anti-transferrin receptor sFv.

Cytotoxic ribonuclease chimeras. Targeted tumoricidal activity in vitro and in vivo.

Toxicity of an antitumor ribonuclease to Purkinje neurons