Inhibition of the Growth and Development of a Transplantable Murine Melanoma by Vitamin A

Felix, Edward L.; Loyd, Betty C.; Cohen, M.

doi:10.1126/science.1154026

Cited by 109 publications

(36 citation statements)

References 8 publications

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“…antitumor immunity in vivo, detected in mice immunized with syngeneic tumors and subse- quently challenged with viable cells of the immunizing tumor, was substantially increased in mice that had been fed a diet enriched in VAOAc. These results could explain previous reports of inhibition of the growth and development, or even regression, of various tumors in animals treated with retinoids or carotenoids (37)(38)(39)(40)(41) and also are compatible with epidemiological data showing that human cancer risks are inversely correlated with blood retinol and with dietary /carotene (42). To study the possible immunopotentiating effect of VAOAc, we used two cloned sarcoma cell lines, one of them (HT3-2.…”

Section: Discussionsupporting

confidence: 91%

Enhancement of specific antitumor immunity in mice fed a diet enriched in vitamin A acetate.

Malkovský¹,

Doré²,

Hunt³

et al. 1983

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

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Age-matched male CBA mice on a conventional or a vitamin A acetate (VAOAc)-rich diet were immunized with irradiated cloned 3-methylcholanthrene-or Harvey sarcoma virus-induced (McSa-I or HT3,2.1) sarcoma cells and then challenged with viable corresponding or unrelated (non-crossreacting) syngeneic sarcoma cells. The survival, of the specifically immunized mice on the VAOAc diet was significantly prolonged in comparison with all control groups of mice as assessed by using logrank tests. Moreover, the specific immunization markedly decreased the incidence of tumors after the McSa-1 (but not HT3-2.1) challenge in a group of mice on the VAOAc diet (5% tumor incidence) compared with-the equivalent group on the control diet (50% tumor incidence). Neither the VAOAc diet nor in vivo immunization alone or combined influenced. natural-killer cell. activity. Specific T-cell-mediated cytotoxicity after in vivo priming and in vitro boosting with sarcoma cells was increased in VAOAcfed mice. However, the marginal increase in cytotoxicity does not in itself explain the strikingly increased resistance to tumor transplants in preimmunized mice on the VAOAc diet in comparison with preimmunized mice on the control diet. The results indicate that a diet enriched in VAOAc can modify the ability of the immune system of a mouse to respond effectively to tumor antigens and can influence whether a tumor grows or regresses.A connection between the risk of cancer and a substance discovered in the beginning of this century (1-4) and subsequently named vitamin A (5) was revealed in 1926 when susceptibility to carcinomas of the stomach in rats fed a vitamin Adeficient diet was observed (6). Since that time, a vast literature suggesting that vitamin A and retinoids (naturally occurring and synthetic derivatives of vitamin A) generally retard or prevent malignant transformation, suppress tumor promotion, or even cause reversion of transformed cells and regression of certain tumors has accumulated (reviewed in refs. 7 and 8). The mechanisms of these manifold anticancer effects are still conjectural (7,8). However, re-tinoid substances can also act as potent immunoregulatory agents (9-18). It has been proposed, but not supported experimentally, that, besides any direct anticancer activity retinoids might exercise, their antitumor effect might be an outcome of the enhancement of host antitumor immune responses (18)(19)(20)(21).This view has been upheld by in vitro studies by Dennert et al. (22) who have shown an augmented antitumor cytotoxic activity of splenic T lymphocytes in mice injected with retinoic acid. Moreover, using the tumor-cell neutralization (Winn)

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Section: Discussionsupporting

confidence: 91%

Enhancement of specific antitumor immunity in mice fed a diet enriched in vitamin A acetate.

Malkovský¹,

Doré²,

Hunt³

et al. 1983

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

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“…Recently, vitamin A was shown to suppress the induction and development of tumors in response to chemical carcinogens (2) and to have an antitumor action in mice inoculated with murine melanoma cells (3). The bases for these actions are unknown, but the ability to control cellular differentiation is undoubtedly involved in the suppression of carcinogenesis.…”

mentioning

confidence: 99%

Retinoic acid (vitamin A acid) induced transcriptional control of interferon production.

Blalock¹,

Gifford²

1977

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

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The production of interferon was used to study the site and mechanism of action of retinoic acid (vitamin A). The data are consistent with a site of action at the gene level, because it appears that interferon production is blocked at the transcriptional step by a retinoic acid-induced protein. (i) The effect of retinoic acid is probably on an early cellulr function associated with interferon production rather than an effect on the inducer [virus or poly(I)poly(C)J. (ii) The suppression of interferon production by retinoic acid is blocked by cycloheximide, indicating that a newly synthesized protein (repressor) mediates the suppression. (iii) When allowances are made for the time required for the synthesis of the retinoic acid-induced protein, the time course of retinoic acid suppression of interferon production is superimposable on the time course of actinomycin D suppression because the slopes are parallel. These data provide evidence for transcriptional control of a specific protein (interferon) by retinoic acid. Additionally, they support the existence of transcriptional control of interferon production after addition of inducer.Vitamin A is known to induce and control cellular differentiation in many tissues (1). Recently, vitamin A was shown to suppress the induction and development of tumors in response to chemical carcinogens (2) and to have an antitumor action in mice inoculated with murine melanoma cells (3). The bases for these actions are unknown, but the ability to control cellular differentiation is undoubtedly involved in the suppression of carcinogenesis. We have shown that vitamin A acid (retinoic acid) restores density-dependent growth control to a transformed cell line (mouse L-929 cells) (4). This finding suggests that the antitumor action of vitamin A may result from a direct effect of the vitamin that restores normal functions to transformed cells. It is important to understand the mechanism(s) by which vitamin A regulates gene expression. One approach to this problem is to study the effect of vitamin A on a cellular molecule that is inducible in vitro.For a number of reasons, interferon synthesis offers a model for the study of mammalian gene expression. First, it is a molecule that is easily inducible in almost every nucleated mammalian cell. Second, after induction, interferon synthesis is thought to be controlled by specific regulatory protein(s) (repressors) (5-7). Interestingly, these putative repressors are almost exclusively demonstrable in normal (diploid) cells rather than in cell lines and might be thought of as a marker of normalcy. Finally, interferon action results from the induction of another cellular protein (8,9). Because interferon action as well as interferon production results from a derepression event, the comparative effect on the two derepressions could be used to monitor the specificity of the control mechanism(s).We have previously shown that retinoic acid suppresses in-The costs of publication of this article were defrayed in part by the payment of page c...

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“…plantable tumors [6. 14], This activity ap pears to be a result of two modes of action: (a) a direct effect on cell differentiation and tumor growth [ 12,20] and (b) stimulation of host antitumor responses [6,12,14], In mice, the immunomodulating properties of reti noids have included enhancement of anti body responses [3. 10], augmentation of the induction of cytotoxic T cells [4.…”

Section: Introductionmentioning

confidence: 99%

Augmentation of Human Thymocyte Proliferative Responses by Retinoic Acid

Sidell¹,

Famatiga²,

Golub³

1981

Pathobiology

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When 10^–5 to 10^-7M all-trans retinoic acid (RA) was added to human thymocyte or tonsil lymphocyte cultures in the presence of mitogens or allogeneic stimulator cells, blastogenesis was increased up to 2.5-fold. No augmentation in proliferative responses of peripheral blood or spleen lymphocytes was observed. In the thymus, lymphocytes in the subclass of cells that did not bind peanut agglutinin (PNA) were responsible for the RA-induced enhancement. RA also increased the number of mitogen-stimulated thymocyte colonies developing in soft agar. These results indicate that the targets of RA activity must be lymphoid cells at a later stage of maturation than those identified by binding to PNA, and that one mechanism of RA enhancement is an increase in the number of lymphocytes that undergo blast transformation.

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Inhibition of the Growth and Development of a Transplantable Murine Melanoma by Vitamin A

Abstract: Vitamin A, given either orally or intraperitoneally, has a dramatic inhibitory effect on the growth and development of a highly immunogenic murine melanoma. This effect may be due to enhancement of antitumor immunity by vitamin A.

Cited by 109 publications

References 8 publications

Enhancement of specific antitumor immunity in mice fed a diet enriched in vitamin A acetate.

Enhancement of specific antitumor immunity in mice fed a diet enriched in vitamin A acetate.

Retinoic acid (vitamin A acid) induced transcriptional control of interferon production.

Augmentation of Human Thymocyte Proliferative Responses by Retinoic Acid

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