Retinoid Derivatives Research Articles

Harlequin Infant Born to a Varicella Infected Mother: A Case Report

Harlequin ichthyosis is a rare, severe form of congenital ichthyosis characterised by distinct physical appearance of the infant. It has occurrence of 1 in 1 million births and over 100 cases have been reported so far. It is caused by mutation in ABCA12 gene involved in lipid transport leading to profound thickening of stratum corneum. The mainstay of management relies on supportive care & administration of retinoid derivatives. Outcome is usually fatal and most of the babies die during neonatal period. In this article, we report a case of harlequin baby born of non-consanguineous marriage with history of chicken pox in the mother during first trimester of pregnancy.

Combining a BCL2 Inhibitor with the Retinoid Derivative Fenretinide Targets Melanoma Cells Including Melanoma Initiating Cells

Investigations from multiple laboratories support the existence of melanoma initiating cells (MICs) that potentially contribute to melanoma's drug resistance. ABT-737, a small molecule BCL-2/BCL-XL/BCL-W inhibitor, is promising in cancer treatments, but not very effective against melanoma, with the anti-apoptotic protein MCL-1 as the main contributor to resistance. The synthetic retinoid fenretinide (4-HPR) has shown promise for treating breast cancers. Here, we tested whether the combination of ABT-737 with 4-HPR is effective in killing both the bulk of melanoma cells and MICs. The combination synergistically decreased cell viability and caused cell death in multiple melanoma cells lines (carrying either BRAF or NRAS mutations), but not in normal melanocytes. The combination increased the NOXA expression and caspase-dependent MCL-1 degradation. Knocking-down NOXA protected cells from combination-induced apoptosis, implicating the role of NOXA in the drug synergy. The combination treatment also disrupted primary spheres (a functional assay for MICs) and decreased the percentage of ALDHhigh cells (a marker of MICs) in melanoma cell lines. Moreover, the combination inhibited the self-renewal capacity of MICs, measured by secondary sphere forming assays. In vivo, the combination inhibited tumor growth. Thus, this combination is a promising treatment strategy for melanoma, regardless of mutation status of BRAF or NRAS.

Supplementation with vitamin a derivatives to rescue vision in animal models of degenerative retinal diseases.

The perception of light begins when photons reach retinal tissue located at the back of the eye and photoisomerize the visual chromophore 11-cis-retinal to all-trans-retinal within photoreceptor cells. Isomerization of 11-cis-retinal activates the protein rhodopsin located in photoreceptor outer segments, thereby inducing a phototransduction cascade leading to visual perception. To maintain vision, 11-cis-retinal is regenerated in the retinal pigmented epithelium (RPE) via the visual cycle and delivered back to the photoreceptor cells where it may again bind to rhodopsin. Distinct pathological mechanisms have been observed to contribute to inherited retinal degenerative diseases including severe delay in 11-cis-retinal regeneration and delayed clearance of all-trans-retinal, which leads to the accumulation of harmful retinoid by-products. In the last decade, our group has conducted several proof-of-concept (POC) studies with retinoid derivatives aimed at developing treatments for retinal degenerative diseases caused by an impaired visual cycle. Here, we will introduce experimental procedures, which have been developed for POC studies involving retinoid biology.

Nanoencapsulation of Fenretinide in Glucosamine Butyrate - Gelatin Matrices as a Mean to Improve its Oral Bioavailability

Fenretinide (4-HPR) is the most promising retinoid derivative with anticancer activity and low toxicity profile. Despite its excellent tolerability, the formulations of 4-HPR that have been clinically evaluated until now have not provided drug plasma concentrations suitable to elicit a therapeutic response. Therefore innovative formulations able to improve the drug bioavailability would be of considerable interest. In this work we describe the preparation and functional evaluation of novel nanocapsules designed to enhance fenretinide bioavailability by oral route through the use of glucosamine butyrate as bioavailability enhancer and gelatin as a matrix forming agent. The anti-tumour activity of the nanocapsules has been tested in in vitro and in vivo models either in feeding and fasting conditions. Our data indicated that after oral administration the nanocapsules provide 4-HPR plasma concentrations in the range compatible with the antitumor activity as assessed in vitro expecially in fasting conditions. Moreover these novel nanocapsules have proved to be effective in tumor xenografts after oral administration.

Structures of holo wild-type human cellular retinol-binding protein II (hCRBPII) bound to retinol and retinal.

Cellular retinol-binding proteins (CRBPs) I and II, which are members of the intracellular lipid-binding protein (iLBP) family, are retinoid chaperones that are responsible for the intracellular transport and delivery of both retinol and retinal. Although structures of retinol-bound CRBPI and CRBPII are known, no structure of a retinal-bound CRBP has been reported. In addition, the retinol-bound human CRBPII (hCRBPII) structure shows partial occupancy of a noncanonical conformation of retinol in the binding pocket. Here, the structure of retinal-bound hCRBPII and the structure of retinol-bound hCRBPII with retinol fully occupying the binding pocket are reported. It is further shown that the retinoid derivative seen in both the zebrafish CRBP and the hCRBPII structures is likely to be the product of flux-dependent and wavelength-dependent X-ray damage during data collection. The structures of retinoid-bound CRBPs are compared and contrasted, and rationales for the differences in binding affinities for retinal and retinol are provided.

Abstract 2604: Characterization of the activity and the mechanism of action of the new retinoid derivative ST5589 in pre-clinical models of lymphomas: involvement of MYC and cell cycle genes

Abstract Innovative and effective treatments are necessary for lymphomas that are common and still deadly cancers for many patients. Atypical retinoids show cytotoxic activity in different pre-clinical tumor models even though their mechanism of action is still largely unclear. Here, we report activity and mechanistic data with ST5589 (adarotene derivative), an active representative of this new class of agents (1), in pre-clinical lymphoma models. Methods. Cell lines from diffuse large B-cell lymphoma (DLBCL, n=17), mantle cell lymphoma (MCL, n=4), splenic marginal zone lymphoma (SMZL, n=3) underwent 72 hr exposure to increasing doses of ST5589 (Sigma Tau, Pomezia, IT) to assess anti-proliferative activity by MTT assay. Apoptosis was assessed by Annexin-V/7-AAD staining. Gene expression profiling (GEP) was done with Illumina HumanHT-12 Expression BeadChips at baseline on all cell lines and, in triplicate, on 1 ABC- (TMD8) and 1 GCB-DLBCL (DOHH2) cell line treated with 300 nM ST5589 or DMSO for 8 hrs. Cell lines with IC50 < than the median were defined as sensitive. GEP/IC50 correlation was assessed by Pearson correlation. Differential expression analysis was performed with LIMMA, GSEA, Metacore. Results. Median IC50 was 235 nM (91-2652) for all the cell lines without significant differences among histological subtypes or between GCB- and ABC-DLBCL: DLBCL, 269 (97-2652); GCB-DLBCL 250, (97-1684); ABC-DLBCL, 531 (181-2625); MCL, 237 (91-401); SMZL, 144 (135-203). ST5589 induced apoptosis in 4/5 DLBCL cell lines (DOHH2, TMD8, SU-DHL-2, VAL). GEP in two DLBCL treated with ST5589 or DMSO was performed, and ST5589 significantly affected transcripts involved in multiple cell cycle-related gene-sets. Aurora kinase A coding gene was one of the most down-regulated. MYC translocation was associated with lower IC50 (P 0.045) and higher number of responders (P 0.021). Transcripts associated with resistance to ST5589 were significantly enriched of genes involved in MYD88/TLR/STAT3 signaling and MAPK pathway, while transcripts associated with sensitivity were enriched of MYC target genes, genes high in Burkitt lymphoma, and involved in cellular respiration, and proteoglycan biosynthesis. Conclusions. ST5589 showed anti-proliferative and cytotoxic preclinical activity in lymphoma, affecting cell-cycle regulation. While MYD88, TLR, STAT3 and MAPK pathways activation correlated with reduced drug activity, MYC deregulation was associated with sensitivity to ST5589. Our data, together with direct cytotoxicity and immune-system mediated activity reported for the parent compound adarotene ST1926 (2), make ST5589 worth of further studies in MYC-driven lymphomas as a representative of the innovative therapeutic class of atypical retinoids. References 1 Giannini et al. Bioorganic and Med Chemistry 2012, 20: 2405-15 2 Pisano et al. Proceedings AACR 2004 Abstract #2075 Citation Format: Elena Bernasconi, Ivo Kwee, Andrea Rinaldi, Luciano Cascione, Maurilio Ponzoni, Loredana Vesci, Giuseppe Giannini, Anastasios Stathis, Emanuele Zucca, Eugenio Gaudio, Francesco Bertoni. Characterization of the activity and the mechanism of action of the new retinoid derivative ST5589 in pre-clinical models of lymphomas: involvement of MYC and cell cycle genes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2604. doi:10.1158/1538-7445.AM2014-2604

In Vitro Assessment of the Tolerance Profile, the Metabolism and the Potential Depigmenting Activity of New Retinoid Derivatives

In spite of the numerous depigmenting agents available, there is an inverse relationship between safety and efficiency. Natural retinoids exert depigmenting activities in vivo, but have a narrow therapeutic window. There is thus a need for a new class of depigmenting agents that would be both safe and useful. The aim of the study was to analyse the potential interest of new retinoid derivatives as topical depigmenting agents.

Encapsulation in lipid-core nanocapsules overcomes lung cancer cell resistance to tretinoin

Tretinoin is a retinoid derivative that has an antiproliferative effect on several kinds of tumours. Human lung adenocarcinoma epithelial cell lines (A549) exhibit a profound resistance to the effects of tretinoin. Nanocarriers seem to be a good alternative to overcomecellular resistance to drugs. The aim of this study was to test whether tretinoin-loaded lipid-core nanocapsules exert anantitumor effect on A549 cells. A549 cells were incubated with free tretinoin (TTN), blank nanocapsules (LNC) and tretinoin-loaded lipid-core nanocapsules (TTN–LNC). Data from evaluation of DNA content and Annexin V binding assay by flow cytometry showed that TTN–LNC induced apoptosis and cell cycle arrest at the G1-phase while TTN did not. TTN–LNC showed higher cytotoxic effects than TTN on A549 cells evaluated by MTT and LIVE/DEAD cell viability assay. Gene expression profiling identified up-regulated expression of gene p21 by TTN–LNC, supporting the cell cycle arrest effect. These results showed for the first time that TTN–LNC are able to overcome the resistance of adenocarcinoma cell line A549 to treatment with TTN by inducing apoptosis and cell cycle arrest, providing support for their use in applications in lung cancer therapy.

Synthesis and Biological Evaluation of New Retinoid Derivatives

The key intermediate boronic acid 2 was synthesized via sequential reactions of Friedel-Crafts alkylation, bromi- nation and nucleophilic reaction by using anisole as starting material. Hydroxyacetone was converted to bromide compound 3 by the Wittig reaction, bromination, Arbuzov reaction and Horner-Wadsworth-Emmons (HWE) reaction. Three novel retinoid derivatives 1a~1c can be obtained via the Suzuki coupling reaction of the boronic acid 2 with bromide compound 3, methyl 4-bromo-2-fluorobenzoate (4) or methyl 6-bromonicotinate (5) and followed by hydrolysis of the corresponding esters. In addition, trifluoromethyl substituted retinoid derivative 1d was synthesized via sequential reactions of Friedel-Crafts alkyla- tion, nitration, trifluoromethylation, reduction and nucleophilic reaction with bromobenzene as strarting material. The struc- tures of four new retinoid derivatives 1a~1d were confirmed by 1 H NMR, 13 C NMR, IR and HRMS analyses. Furthermore, the inducing differentiation abilities of molecules 1a~1d for HL-60 cells were tested, and the results revealed that these four retinoid derivatives are biological active. The IC50 values of fluorinated derivatives 1b and 1d are lower than that of commer- cial medicine all trans retinoid acid (ATRA). Keywords retinoid derivative; synthesis; organofluorine compounds; antineoplastic

Retinyl retinoate, a retinoid derivative improves acne vulgaris in double-blind, vehicle-controlled clinical study

Topical retinoids have been an important therapy used in the treatment of acne. However, retinoids often have adverse effects that range from mild to moderate local irritation. Retinyl retinoate is a member of a new generation of well-tolerated synthetic retinoids used as a topical retinoid treatment. To assess retinyl retinoate 0.05% for acne vulgaris therapy, fifteen female patients with mild to moderate facial acne prevalence were included in a double-blind, placebo-controlled, split-face trial for 8 weeks by investigators and measurement of sebum amount. In addition, retinyl retinoate was measured in anti-bacterial efficacy by an agar plate diffusion assay. Retinyl retinoate showed a significant decrease in both inflammatory and non-inflammatory lesions, and in sebum amount at 8 weeks (P < 0.05). The application of retinyl retinoate is effective and no local side effects for acne lesions. Retinyl retinoate had somewhat anti-bacterial activity against Propionibacterium acnes (P. acnes). These results indicate that retinyl retinoate can be used as treatment for mild acne or could potentiate the efficiency of an additive anti-acne agent. Retinyl retinoate is possible to be suggested as a topical anti-acne treatment with excellent tolerance.

Anti-tumor effect of 4-Amino-2-Trifluoromethyl-Phenyl Retinate on human breast cancer MCF-7 cells via up-regulation of retinoid receptor-induced gene-1

4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR) is one of the retinoid derivatives designed and synthesized in our team. In this paper, we explored the potential anti-tumor effects of ATPR in breast cancer. Here we found that ATPR showed remarkable anti-proliferative effects in a dose- and time-dependent manner, caused cell cycle arrest in the G0/G1 phase and significantly increased the expression of retinoid receptor-induced gene-1 (RRIG1). ATPR decreased the expression of phosphorylation-ERK (p-ERK) and increased the expression of estrogen receptor β (ERβ) and phosphorylation-p38 (p-p38). Following RRIG1 knockdown by RNAi interference, we found that the changes of ERβ, p-ERK and p-p38 induced by ATPR were both depressed. Our data suggest that ATPR could inhibit the proliferation and induce differentiation of MCF-7 cells via mediating the expression of RRIG1.

Abstract 842: Role of Galectin-3 in invasive and apoptotic properties of neuroblastoma cells.

Abstract Background: Neuroblastoma (NB) is a childhood cancer derived from the neural crest stem cells. It generally progresses to an aggressive therapy resistant, fatal metastatic tumor. MYCN over-expression and amplification, and increased BDNF/TrkB signaling are used as signatures of high-risk NB. However, only about 25% of malignant tumors display these features. Thus, the identification of additional biomarkers and therapeutic targets is essential. Up-regulation of Galectin 3 (Gal-3), a multifunctional, carbohydrate binding cytokine has been extensively correlated with highly malignant behavior and poor prognosis of many cancers. However, the role of Gal-3 in NB is largely unknown. In this study, we investigated the expression pattern of Gal-3 in a panel of NB cell lines and examined whether silencing of Gal-3 expression by means of a siRNA approach decreases their invasive properties, and increases their sensitivity to pro-apoptotic chemotherapeutic drug, fenretinide (4-HPR), a synthetic retinoid derivative. Materials and Methods: We utilized RT-PCR gene expression analysis, RNA interference approaches, western blot and immunofluorescence analysis, scratch technique, transwell Boyden chamber migration assay, colony forming assay, and cytokine antibody array screening to address these studies. Results: Gal-3 expression is differentially regulated in TrkB-positive, MYCN-amplified (SMS-KCNR and SK-N-BE) and TrkB-negative, non-MYCN-amplified (SK-N-AS, SK-N-SH, and SH-SY5Y) NB cell lines. Gal-3 expression was significantly higher in SK-N-AS cells that are of glial sub-lineage. Gal-3 was expressed both in cytoplasm and membrane. On the other hand, Gal-3 expression was relatively lower in less invasive, non-tumorigenic SK-N-SH cells. Silencing of Gal-3 by a small-interfering RNA against Gal-3 (Gal-3-SiRNA) decreased the colony forming potential, in vitro migratory and angiogenic abilities of SK-N-AS cells. Pre-treatment with Gal-3 SiRNA increased the sensitivity of SK-N-AS cells to 4-HPR induced apoptosis. Furthermore, exogenous Gal-3 treatment in neuroblast like Neuro-2a cells resulted in the up-regulation of IL-6 and phosphorylation of the pro-survival molecule AKT. Discussion: Our data suggest that Gal-3 mediates migratory and invasive phenotype of non-MYCN amplified NB derived cells possibly via regulating the IL-6 signaling and Akt phosphorylation. Silencing of Gal-3 may be potentially useful to suppress the resistance of NB cells to apoptosis. Citation Format: Umadevi V. Wesley, Esat Resad, Robert J. Dempsey. Role of Galectin-3 in invasive and apoptotic properties of neuroblastoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 842. doi:10.1158/1538-7445.AM2013-842

Retinoid derivatives offer anti‐inflammatory benefits by promoting neutrophil apoptosis and inhibiting proinflammatory mediator production in a model of bovine respiratory disease

Clearance of apoptotic neutrophils (PMN) following infection is critical for the resolution of inflammation. Despite demonstrating immunomodulatory properties, the effects of retinoids in PMN in the context of an inflammatory response remain unknown.Objectiveto evaluate the immunomodulatory properties of two retinoids, oxidatively‐transformed carotene‐β (OxC‐β) and retinoic acid (RA) in a model of Mannheimia haemolytica‐induced bovine respiratory disease, which is characterized by severe inflammation.Resultsin vitro, RA and OxC‐β induced caspase‐and time‐dependent apoptosis, but not necrosis, in bovine PMN, but not epithelial cells or fibroblasts. Neither RA nor OxC‐β affected PMN function. In M. haemolytica‐infected calves (2×107 CFU), animals that received a 28‐day dietary OxC‐β treatment (10 mg/kg) had elevated apoptotic leukocytes and reduced LTB4 levels in their lower airways 3h post‐infection vs infected‐untreated calves.ConclusionRA and OxC‐β promote cell‐specific apoptosis and inhibit the production of pro‐inflammatory LTB4, both mechanisms that promote the resolution of inflammation, thereby suggesting an anti‐inflammatory role for retinoid derivatives. Supported by NSERC and AIHS.

Synthesis, anticancer activities and molecular modeling studies of novel indole retinoid derivatives

In this study, novel (E)-3-(5-substituted-1H-indol-3-yl)-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (5(a–e)) derivatives were synthesized and their anticancer effects were determined in vitro. Novel indole retinoid compounds except 5e have anti-proliferative capacity in liver, breast and colon cancer cell lines. This anti-proliferative effect was further analyzed in breast cancer cell line panel by using the most potent compound 5a. It was determined that 5a can inhibit proliferation at very low IC50 concentrations in all of the breast cancer cell lines. Here, we present some evidence on apoptotic termination of cancer cell proliferation which may be primarily driven by the inhibition of RXRα and, to a lesser extent, RXRγ.

Anti‐inflammatory benefits of retinoids: retinoic acid and oxidatively‐transformed β‐carotene induce neutrophil apoptosis and inhibit leukotriene B4 synthesis

Clearance of apoptotic neutrophils following infection is critical for the resolution of inflammation. Little is known about the effects of retinoid products (vitamin A derivatives) in innate immune cells in the context of an inflammatory response.HypothesisRetinoic acid (RA) or oxidatively‐transformed β‐carotene (OxβC), a retinoid derivative, may have immuno‐modulatory benefits by promoting neutrophil apoptosis and inhibiting proinflammatory signaling.AimTo evaluate the effects of RA and OxβC in model of Mannheimia haemolytica‐induced bovine respiratory disease, a disease associated with severe inflammation.ResultsIn vitro, RA and OxβC dose‐dependently induced apoptosis, but not necrosis, in circulating bovine neutrophils, but not in epithelial cells. In M. haemolytica‐challenged calves (2×107 CFU), animals that received a 28‐day dietary OxβC treatment (10 mg/kg) had elevated apoptotic leukocytes and reduced LTB4 levels in their lower airways 3 h post‐infection versus infected‐untreated calves.ConclusionRA and OxβC promote cell‐selective apoptosis and inhibit the synthesis of proinflammatory LTB4, which in turn may confer yet unrecognized anti‐inflammatory benefits. Supported by NSERC.

Vitamin A: History, Current Uses, and Controversies

Vitamin A is required for the proper functioning of many important metabolic and physiologic activities, including vision, gene transcription, the immune system and skin cell differentiation. Both excessive and deficient levels of vitamin A lead to poor functioning of many human systems. The biologically active form, retinoic acid, binds to nuclear receptors that facilitate transcription that ultimately leads to it's physiological effects. Retinoids are derivatives of vitamin A that are medications used to treat acne vulgaris, psoriasis, ichthyosis (and other disorders of keratinization), skin cancer prevention as well as several bone marrow derived neoplasias. Systemic retinoids are teratogenic and have to be prescribed with caution and close oversight. Other potential adverse events are controversial. These include the relationship of retinoid derivatives in sunscreens, their effects on bone mineral density, depression and suicidal ideation and inflammatory bowel disease. These controversies will be discussed in detail.

New retinoid derivatives as back-ups of Adarotene

Adarotene belongs to the so-called class of atypical retinoids. The presence of the phenolic hydroxyl group on Adarotene structure allows a rapid O-glucuronidation as a major mechanism of elimination of the drug, favoring a fast excretion of its glucuronide metabolite in the urines. A series of ether, carbamate and ester derivatives was synthesized. All of them were studied and evaluated for their stability at different pH. The cytotoxic activity in vitro on NCI-H460 non-small cell lung carcinoma and A2780 ovarian tumor cell lines was also tested. A potential back-up of Adarotene has been selected to be evaluated in tumor models.

The Effects of 5-fluorouracil Alone and in Combination with 13-cis Retinoic Acid and Vitamin D3 on Human Oral Squamous Cell Carcinoma Lines

Oral squamous cell carcinoma (OSCC) is responsible for about 90% of oral malignancies and its incidence is increasing. Despite various treatment protocols, survival rate of OSCC is low. Chemotherapy that is used for treating this carcinoma in advanced stages is systemic therapy that destroys carcinogenic cells, and controls tumor metastasis. Chemotherapy is very toxic and has limitations, especially for patients in advanced stages. Considering positive effects of retinoid and vitamin D3 derivatives in treating some carcinomas, we decided to evaluate the effect of combination of these drugs on OSCC. In this study the effects of combination of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 on cultured cell of OSCC have been evaluated. OSCC cells were cultured in culture media and different concentration of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 were added to cultured cell as separately and in combinations. The effect of treatment on cell proliferation and induction of apoptosis were evaluated by MTT and TUNEL assays respectively. Combination of 5-fluorouracil and 13- cis retinoic acid had the highest inhibitory effect on SCC cell proliferation. Combination of two drugs had more apoptotic effect than each of them separately, and combination of three drugs had more effect than combination of two drugs. Because combination of drugs had more inhibitory effect on cell proliferation than one of them and combination of three drugs had the most apoptotic effect than one of these drugs separately, these drugs may have synergic effect on OSCC. Combination of three drugs has more inhibitory effect on cell proliferation and apoptotic effect than one of these drugs.

ChemInform Abstract: Synthesis of a New C‐15 Phosphorus Ylide Used for the Preparation of Some β‐End‐Group Retinoid Derivatives.

AbstractThe new ylide (III) can be easily obtained in two steps from β‐ionone and is stable at ‐20 °C for several months.

Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta analysis.

BackgroundDespite reported antiproliferative activity of vitamin A and its common use for cancer, there is no comprehensive synthesis of its safety and efficacy in lung cancers. To address this issue we conducted a systematic review of the safety and efficacy of vitamin A for the treatment and prevention of lung cancers.Methods and FindingsTwo independent reviewers searched six electronic databases from inception to July 2009 for clinical, observational, and preclinical evidence pertaining to the safety and efficacy of vitamin A and related retinoids for lung cancers. 248 studies were included for full review and analysis. Five RCTs assessed treatment of lung cancers, three assessed primary prevention, and three looked at secondary prevention of lung cancers. Five surrogate studies, 26 phase I/II, 32 observational, and 67 preclinical studies were also included. 107 studies were included for interactions between vitamin A and chemo- or radiation- therapy. Although some studies demonstrated benefits, there was insufficient evidence overall to support the use of vitamin A or related retinoids for the treatment or prevention of lung cancers. Retinyl palmitate combined with beta carotene increased risk of lung cancer in smokers in the large CARET trial. Pooling of three studies pertaining to treatment and three studies on secondary prevention revealed no significant effects on response rate, second primary tumor, recurrence, 5-year survival, and mortality. There was a small improvement in event free survival associated with vitamin A compared to controls, RR 1.24 (95% CI 1.13–1.35). The synthetic rexinoid bexarotene increased survival significantly among a subset of patients in two RCTs (p<0.014, <0.087).ConclusionsThere is a lack of evidence to support the use of naturally occuring retinoids for the treatment and prevention of lung cancers. The rexinoid bexarotene may hold promise for use among a subset of patients, and deserves further study.