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PubMed1997

Polyenylidene thiazolidinedione derivatives with retinoidal activities.

Several polyenylidene thiazolidine or 2-thioxo-4-thiazolidinone derivatives were synthesized and their retinoidal activities were examined in terms of the differentiation-inducing ability towards human promyelocytic leukemia HL-60 cells and inhibitory effect on interleukin (IL)-1 alpha-induced IL-6 production in MC3T3-E1 cells. Compounds containing a trimethylcyclohexenyl ring induced HL-60 cell differentiation with weaker activity than retinoic acid (1a) by one or two orders of magnitude. The thiazolidinedione derivatives (2, 5, 7) showed stronger activity than the corresponding 2-thioxo-4-thiazolidinone derivatives (3, 6, 8). The effects of a retinoid antagonist (LE540) and synergists (retinoid X receptor (RXR) agonists, HX600 or HX630) on the activities of thiazolidine derivatives indicate that these compounds elicit their activities through the nuclear retinoic acid receptors (RARs). All the thiazolidines examined also inhibited IL-1 alpha-induced IL-6 production with IC50 values of 10 nM order. The retinoidal activities of the thiazolidines are significant, considering that replacement of the carboxylic acid in retinoid structures with bioisosteric functional groups is generally ineffective, as seen in the structure-activity relationships of retinoidal benzoic acids.

Cell Differentiation↗
PubMed2000

Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids.

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.

Animals↗
PubMed2002

Retinoids and cardiovascular developmental defects.

Vitamin A and related retinoids are critical regulators of normal cardiovascular development. Extreme variations in retinoid levels, too little or too much, dramatically alter embryonic morphogenesis that has teratogenic consequences, including effects on the heart and great vessels. Specific cardiovascular targets of retinoid action include effects on the anteroposterior patterning of the early heart, left-right decisions and cardiac situs, endocardial cushion formation, and, in particular, the neural crest. The cardiovascular defects produced are remarkably similar in deficiency and excess, suggesting modulation of common developmental or cellular processes by different levels of retinoids. The isolation of nuclear receptors that mediate retinoid action has led to the identification of some genes directly involved in the regulation of these processes and other gene products that may be affected more indirectly. This review will examine the mechanism of retinoid action, the requirements for vitamin A during normal heart development, and the consequences of nonphysiologic or teratogenic exposure.

Animals↗
PubMed2005

Efficacy and safety of oral retinoids in psoriasis.

With the advent of new biological agents, interest in the treatment of psoriasis has been renewed. Vitamin A and its derivatives (retinoids) have been used successfully in the treatment of psoriasis for over 30 years. In this paper, data on the efficacy and safety of oral retinoids for the treatment of various forms of psoriasis is reviewed. Studies have shown that retinoids are particularly effective in the treatment of pustular and palmoplantar psoriasis. When used in conjunction with ultraviolet therapy, retinoids appear to have a synergistic effect and can be used safely as long-term maintenance therapy. The most common side effects of oral retinoids are usually modest, treatable or reversible, and predominantly affect the liver, musculoskeletal and neurological systems. Potential teratogenicity remains the primary concern with use in women. Oral retinoids appear to be well tolerated in paediatric and HIV-infected patients.

Abnormalities, Drug-Induced↗
PubMed2002

Evolution of the visual cycle: the role of retinoid-binding proteins.

The trafficking of retinoids in the retina represents a model to study soluble hormone-binding proteins in a complex system subject to profound evolutionary adaptations. Although a remarkable illustration of convergent evolution, all visual systems detect light in the same way, that is through the photoisomerization of an 11-cis retinoid to a corresponding trans isomer. What is strikingly different between the systems, is the mechanism by which the 11-cis chromophore is reformed and visual pigment regenerated in a process known as the visual cycle. The variations of the cycle address a problem inherent to retinoids themselves. That is, the properties that make these molecules suited for light detection also account for their susceptibility to oxidative and isomeric degradation, and cellular toxicity. The cycle therefore provides an opportunity to examine the role of soluble hormone-binding proteins within an integrative and evolutionary context. The present review focuses on interphotoreceptor retinoid-binding protein (IRBP), a controversial glycolipoprotein that recruits a protein fold common to Cterminal-processing proteases and the crotonase family. This unorthodox retinoid-binding protein is entrapped in the subretinal compartment of those eyes that translocate visual cycle retinoids between the photoreceptors and the retinal pigment epithelium. Recent studies suggest that we should look beyond a strictly carrier function if we are to appreciate the role of IRBP in the visual cycle. Here we draw lessons from other soluble hormone-binding proteins to anticipate avenues of future research likely to provide insight into the structure and function of IRBP in vision.

Amino Acid Sequence↗
PubMed2006

[Retinoid therapy for autoimmune diseases].

Retinoid is a collective term for compounds which bind to and activate retinoic acid receptors (RARalpha, beta, gamma and RXRalpha, beta, gamma), members of nuclear hormone receptor superfamily. The most important endogeneous retinoid is all-trans-retinoic acid (ATRA) which is an RARalpha, beta and gamma ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and some skin diseases. Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, tamibarotene (Am80) is an RARalpha- and RARbeta-specific (but RARgamma- and RXRs-nonbinding) synthetic retinoid that is effective in the treatment of psoriasis patients and relapsed APL. Experimentally, this compound is also active in animal models of rheumatoid arthritis and experimental autoimmune encephalomyelitis. On this background, possible application of retinoids for the treatment of autoimmune diseases was discussed. In particular, Th1 dominant autoimmune diseases may be the targets of the retinoids.

Animals↗
PubMedDate not supplied

Receptor-independent induction of apoptosis by synthetic retinoids.

Retinoids modulate cell proliferation, differentiation and apoptosis. Many of these effects are mediated by nuclear retinoid receptors. However, studies with certain synthetic retinoids, including some that can activate retinoid receptors, revealed that they affect cell growth and especially apoptosis by mechanisms that are independent of nuclear receptors. This chapter describes the pro-apoptotic effects of the synthetic retinoid CD437 [6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid], and structurally-related retinoids and summarizes the mechanisms by which they induce apoptosis.

Animals↗
PubMed2003

Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites.

Fenretinide (4-HPR) is a retinoid analogue with antitumor and chemopreventive activities. In addition to 4-HPR, there are several other new phenylretinamides bearing hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, and 4 of the terminal phenylamine ring [N-(2-hydroxyphenyl)retinamide (2-HPR), N-(3-hydroxyphenyl)retinamide, N-(2-carboxyphenyl)retinamide, N-(3-carboxyphenyl)retinamide, N-(4-carboxyphenyl)retinamide, and N-(4-methoxyphenyl)retinamide (4-MPR) ]. It is hypothesized that these agents can act independent of the nuclear retinoid receptor pathway. To test this hypothesis directly, we have analyzed the activity of these phenylretinamides in vitro on a panel of F9 murine embryonal carcinoma cell lines, which includes wild-type (F9-WT) and mutant cells that have disrupted genes for both retinoid X receptor alpha and retinoic acid receptor gamma retinoid receptors (F9-KO). The F9-KO cells lack almost all measurable response to all-trans-retinoic acid, the primary biologically active retinoid. Two distinct effects of retinamides were identified. The first is a rapid, dose-dependent induction of cell growth inhibition (reduced cell viability), and the second is a slower induction of differentiation and accumulation of cells in the G(1) phase of the cell cycle that was observed with a concentration of 1 micro M, for only those phenylretinamides bearing charged (hydroxyl or carboxyl) groups on the terminal phenylamine ring. The induction of differentiation and G(1) accumulation was only observed in the F9-WT cells, indicating that this effect is receptor-dependent. 4-MPR, a major metabolite of 4-HPR, lacks a charged group on the terminal phenylamine ring and did not induce retinoid receptor-dependent effects, but did induce cell growth inhibition. Thus, 4-MPR may play a role in the clinical activity of 4-HPR. This study further reveals the mechanism of action of these novel phenylretinamides and supports continued investigation into their development as chemopreventive drugs.

Animals↗
PubMedDate not supplied

Altered retinoid distribution in the repeated epilation (Er) mutant mouse.

The repeated epilation (Er) mutation in mice causes successive loss and regrowth of hair in heterozygotes (Er/+), and blocks orofacial development and epidermal differentiation in lethal homozygotes (Er/Er). Because the mutation affects a systemic factor, because the Er phenotypes resemble exposure to excess retinoids and because retinoids are critical regulators of epithelial differentiation, we examined whether systemic retinoid levels are altered by the Er defect. Liver retinoic acid and retinol were elevated 1.5- and 3.5-fold, respectively, in adult heterozygotes (Er/+) compared to normal (+/+) animals. Retinyl palmitate was increased 2-fold in heterozygous skin and 3-fold in kidney, but the retinol level in plasma was only half that of normal animals. Newborn heterozygous liver also had nearly 2-fold increased retinoids compared to normal. In contrast, Er/Er newborns had reduced retinoid levels in liver, two-thirds the retinol and 15% the retinyl palmitate compared to normal, but greater than 4-fold elevated levels of retinyl palmitate in the extrahepatic body. Tissue contents of retinol binding protein (RBP), which transports vitamin A from the liver to the remainder of the body, were determined by immunoblotting with anti-mouse RBP. Newborn normal and mutant animals had similar liver microsomal RBP contents. RBP contents in plasma and in liver microsomes were also similar in normal and Er/+ adults despite different retinol contents in the Er/+ tissues. Hair follicles of the Er/+, but not the normal adult, were stained with this antiserum to RPB in the outer root sheath layer. These results strongly suggest that altered retinoid distribution is associated with, and may be responsible for, the altered epithelial differentiation in the Er mutant.

Animals↗
PubMed1991

Immortalization by human papillomavirus type 16 alters retinoid regulation of human ectocervical epithelial cell differentiation.

Human cervical cells are a primary site of papillomavirus infection and 90% of all cervical tumors are positive for human papillomavirus (HPV) DNA. Over one-half million cases of HPV-associated cervical, vulvar, and penile cancers are reported per year. Yet, in spite of the magnitude of this problem, the effects of HPV infection on cervical cell growth and differentiation are not well characterized. To study these effects we have developed a clonal cell line of HPV-16-immortalized ectocervical epithelial cells, ECE16-1. In the present study we demonstrate that under normal growth conditions the cytokeratin content of ECE16-1 cells is dramatically altered compared to normal cervical cells; the level of K5, K6, K14, K16, and K17 is reduced and the level of K7, K8, and K19 is increased. We demonstrate that this change is largely due to a difference in the response of the cells to retinoids, as growth in retinoid-free medium produces a complete normalization of cytokeratin levels. Upon addition of natural and synthetic retinoids, the levels of cytokeratins K5, K6, K14, K16, and K17 are reduced, while the levels of cytokeratins K19, K7, and K8 are increased. Cytokeratin K13 levels are only slightly altered. The level of involucrin, a precursor of the cervical cell envelope (superficial cell), is not changed by immortalization nor is it regulated by retinoids. Transglutaminase activity is also not appreciably altered by immortalization; however, ECE16-1 cells make fewer envelopes than normal ECE cells. Our results clearly indicate that natural and synthetic retinoids suppress the differentiation of HPV transformed cervical cells. In early, low grade, cervical intraepithelial neoplasia, transcription of the HPV16 E6/E7 oncogenes is confined to the suprabasal layers. Our results suggest that retinoids, because they inhibit the differentiation of HPV16 immortalized cervical cells, may reduce the extent of viral oncogene transcription and thus be useful in slowing the neoplastic process.

Cell Differentiation↗
PubMed1991

BMY 30047: a novel topically active retinoid with low local and systemic toxicity.

In the treatment of various dermatological disorders, topically applied retinoids have potential therapeutic use with the advantage of improved localized activity and lower toxicity over systemically administered retinoids. However, most retinoids cause a significant degree of local irritation. In the present study, the ability to produce local activity with low local irritation potential was evaluated with a novel retinoic acid derivative. BMY 30047 (11-cis, 13-cis-12-hydroxymethylretinoic acid delta-lactone) is one of a series of retinoic acid derivatives in which the carboxyl function of the polar end was modified with the aim of achieving reduced local irritation and systemic toxicity while retaining the local therapeutic effect. BMY 30047 was evaluated and compared with all-trans retinoic acid for topical retinoid activity in several preclinical assay systems, including the utricle reduction assay in rhino mice, 12-o-tetradecanoylphorbol 13-acetate ester-stimulated ornithine decarboxylase induction in hairless mice and the UV light-induced photodamaged skin model in hairless mice. BMY 30047 was assessed for retinoid-type side effects by evaluating the skin irritation potential in rabbits after repeated topical application, and hypervitaminosis A-inducing potential in mice after i.p. injection. BMY 30047 demonstrated significant topical retinoid activity in several in vivo models with less skin irritation potential relative to the most used clinical concentrations of all-trans retinoic acid. BMY 30047 also showed very little systemic activity and did not produce any evidence of hypervitaminosis A syndrome at systemic doses 20 times greater than the no-effect dose of all-trans retinoic acid.

Administration, Topical↗
PubMedDate not supplied

New synthetic retinoids: effects on proliferation and differentiation.

Nine retinoid analogues were synthesized and their effects on cell proliferation and differentiation of tumor cell lines were analysed and compared with those of natural retinoids (retinoic acid, retinol, retinal). Our results demonstrate differential inhibitory effects of the synthetic retinoids on cell growth. This inhibitory activity of the synthetic retinoids was, in some cases, higher than that of retinoic acid and retinol. Natural and synthetic retinoids were found to be able to induce to a different extent erythroid differentiation of murine erythroleukemia cells and adipogenic conversion of Chinese Hamster FHO6N1-1 cells. Our data suggest that studies on the relationship between structure and biological activity could be approached by using the analysed synthetic retinoids.

Animals↗
PubMed1988

Effects of dietary retinoid and triglyceride on the lipid composition of rat liver stellate cells and stellate cell lipid droplets.

Hepatic stellate cells store the majority of the liver's retinoid (vitamin A) reserves as retinyl esters in stellate cell lipid droplets. A study was conducted to explore the effects of differences in dietary retinoid and triglyceride intake on the composition of the stellate cell lipid droplets. Weanling rats were placed on one of five diets that differed in retinoid or triglyceride contents. The dietary groups were: 1) control (2.4 mg retinol (as retinyl acetate)/kg diet and 20.5% of the calories supplied by triglyceride (as peanut oil]; 2) low retinol (0.6 mg retinol/kg diet and control triglyceride levels); 3) high retinol (24 mg retinol/kg diet and control triglyceride levels); 4) low triglyceride (2.4 mg retinol/kg diet and 5% of the calories supplied by triglyceride); and 5) high triglyceride (2.4 mg retinol/kg diet and 45% of the calories supplied by triglyceride). Stellate cells were isolated using the pronase-collagenase method and stellate cell lipid droplets were isolated by differential centrifugation. The levels of retinoids and other lipids were measured by high performance liquid chromatography. The stellate cells from control rats contained 113 micrograms total lipid/10(6) cells. Control stellate cell lipid droplets had the following mean percent lipid composition: 39.5% retinyl ester; 31.7% triglyceride; 15.4% cholesteryl ester; 4.7% cholesterol; 6.3% phospholipids; and 2.4% free fatty acids. Both the concentration of stellate cell lipids and the composition of stellate cell lipid droplets were markedly altered by changes in dietary retinoid. The low and high retinol groups contained, respectively, 82 and 566 micrograms total lipid/10(6) cells, with retinyl ester representing, respectively, 13.6% and 65.4% of the lipid present in the stellate cell lipid droplets. Low and high triglyceride groups were similar to controls in both stellate cell lipid content and the composition of the stellate cell lipid droplets. These findings indicate that the composition of stellate cell lipid droplets is strongly regulated by dietary retinoid status but not by dietary triglyceride intake.

Animals↗
PubMed1987

Comparative teratogenic activity of cancer chemopreventive retinoidal benzoic acid congeners (arotinoids).

The benzoic acid derivatives of retinoic acid, often referred to as arotinoids, are synthetic retinoids that possess some of the properties of vitamin A. In general, these retinoids have more favorable therapeutic ratios, based on acute toxicity in adults, than all-trans-retinoic acid in cancer chemoprevention. In the present study, a single dose of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propen-1-yl]benzoic acid (Ro 13-7410; arotinoic acid), ethyl-(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)-1-propen-1-yl]benzoate (Ro 13-6298; arotinoid ethyl ester), (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propen-1-yl]phenylmethanol (Ro 13-8320; arotinoic methanol), or (E)-1,2,3,4-tetrahydro-1,1,4, 4-tetramethyl-6-[1-(4-methylphenyl)-1-propen-2-yl]naphthalene (Ro 13-9272; methyl arotinoid) was administered to pregnant Syrian golden hamsters during the early primitive streak stage of gestation. A significant increase in the numbers of litters containing one or more malformed offspring occurred at all doses of each retinoid studied. The types of malformations induced by oral arotinoid treatment were essentially identical to those found after maternal treatment with all-trans-retinoic acid or other teratogenic retinoids during the same gestational age. The results indicate that the alcohol congener was approximately 400 times more potent on a milligram per kilogram basis than all-trans-retinoic acid as a teratogen, and it was 70 times as embryolethal as all-trans-retinoic acid. The ethyl ester congener was 132 times, and the free acid 123 times, as embryolethal as all-trans-retinoic acid. On a molar basis, the arotinoic acid was at least 375 times as teratogenic as all-trans-retinoic acid and at least 140 times as teratogenic as etretinate in hamsters. Because the dose-response curves for arotinoids were significantly parallel to that for all-trans-retinoic acid, and because the spectrum of congenital defects induced by arotinoids was identical to that induced by all-trans-retinoic acid and other teratogenic retinoids, the mechanism of embryopathic action of these conformationally restricted retinoids was concluded to be similar to that of all-trans-retinoic acid.

Abnormalities, Drug-Induced↗
PubMed1983

Regulation of epidermal transglutaminase activity and terminal differentiation by retinoids and phorbol esters.

A number of characteristics of phorbol ester-mediated mouse skin tumor promotion indicate that cell selection is the underlying biological process. Studies in vivo and in cultured mouse epidermal cells suggest that selection is based on heterogeneous responses of subpopulations of basal cells which can be induced to proliferate or differentiate in response to promoter exposure. Retinoids are effective inhibitors of tumor promotion in mouse skin but do not influence the proliferative response to phorbol esters. Since both retinoids and phorbol esters modify epidermal differentiation, the antipromoter action of retinoids could be related to differentiation responses. Retinoic acid induces transglutaminase activity in cultured mouse epidermal basal cells grown in less than 0.1 mM Ca2+. While this enzyme is associated with terminal differentiation in skin, retinoic acid paradoxically blocks the terminal differentiation of cultured cells. In contrast, phorbol esters and extracellular calcium greater than 0.1 mM induce both transglutaminase activity and terminal differentiation. Enzyme kinetic analyses indicate that the transglutaminases induced by all three inducers are the same enzyme. The increase in activity of transglutaminase by all three inducers requires RNA and protein synthesis. However, the time course of increase and decay of each activity differs for each inducer. A variety of biologically active retinoids induce transglutaminase activity, and their effectiveness correlates with their reported antipromoter activity. Exposures to both retinoic acid and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate are antagonistic resulting in less than additive induction. Induction kinetics with both inducers are more like those of retinoic acid than those of the phorbol ester. Simultaneous exposure to retinoic acid and 12-O-tetradecanoylphorbol-13-acetate protects the epidermal cell population from induced terminal differentiation and cell loss which is observed in response to the promoter alone. These results suggest that the antipromoting action of retinoids could be mediated by modification of phorbol ester-accelerated terminal differentiation through an effect on transglutaminase and cornification. This action of retinoids would block a critical aspect of cell selection involving loss of cells and subsequent regenerative hyperplasia, although simple hyperplasia may still occur.

Acyltransferases↗
PubMed1983

[Use of systemic retinoids in dermatology].

The naturally occurring retinoids (vitamin A alcohol = retinol and all-trans-retinoic acid) have been largely replaced by synthetic retinoids in recent years as systemic drugs for use in dermatology. At the present time, two synthetic retinoids are commercially available: etretinate (Tigason) and isotretinoin (Accutane). These compounds-which have a more favourable therapeutic index than the naturally occurring retinoids-ushered in a new era of dermatological therapy by their potent antikeratinizing, antiseborrhoeic (only isotretinoin) and antineoplastic action. The broadest indications for the use of these retinoids are psoriasis (etretinate) and cystic acne (isotretinoin), whereas the most dramatic effects are encountered in a number of severe ichthyosiform disorders. Another important, although at present not clearly defined role of the retinoids is in the prophylaxis of skin tumours.

Acne Vulgaris↗
PubMed1984

Diazacholesterol-induced ichthyosis in the hairless mouse. Assay for comparative potency of topical retinoids.

Although the new synthetic retinoids are effective when administered systemically, they have not been shown to be effective as topical agents. We compared the topical activity of six synthetic retinoids (two arotinoids, etretinate, all-trans- and 13-cis-tetrazole-retinamide, isotretinoin, and tretinoin) on tail skin in the diazacholesterol-fed mouse model of ichthyosis. Responses were assessed clinically and by measurement of stratum corneum thickness. Although the arotinoids dramatically reduced scaling, they were toxic at concentrations above 0.1%, as was etretinate at 1.0% or greater. Lower concentrations were effective without producing local or systemic toxic reactions. Clinical responses were paralleled by equivalent decrements in stratum corneum thickness, which also permitted quantitative comparisons. The order of potency for the retinoids was as follows: arotinoids, etretinate, tetrazole-retinamides, tretinoin = isotretinoin, vehicle. These results demonstrate that (1) the synthetic retinoids hold promise as topical agents; (2) irritation is not an absolute requirement for topical retinoid activity; and (3) the diazacholesterol-fed mouse offers a new assay of topical retinoid potency in a well-defined animal model of ichthyosis.

Administration, Topical↗
PubMed1995

Human cervical cancer. Retinoids, interferon and human papillomavirus.

Our studies highlight the importance of dietary vitamin A (retinol) and other retinoids in maintaining normal cervical cell function and in inhibiting the growth of cervical tumors. Based on our results we conclude that 1) HPV 16-immortalization enhances cervical cell sensitivity to retinoids, 2) cytokeratin expression may be useful as a marker for evaluating the success of retinoid therapy in vivo, 3) retinoids do not necessarily act to inhibit proliferation of HPV-immortalized cervical cells via effects on HPV E6 and E7 RNA levels and 4) retinoids may act to inhibit cervical proliferation by "suppressing" the activity of the EGF and IGF signalling pathways. Based on these and other results, it is worth considering the possibility that vitamin A or related retinoids could be administered therapeutically, early in the neoplastic process (either systemically or locally), to inhibit the progress of the disease. These results also suggest that combined interferon/retinoid therapy may provide an enhanced beneficial effect to reduce cervical tumor size due to the fact that each agent is inhibiting cervical cell proliferation via distinct, but reinforcing, pathways (i.e., IFN gamma reduces E6/E7 expression, RA inhibits the function of the EGF and IGF1 signalling pathways).

Epidermal Growth Factor↗