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Female Sprague-Dawley rats were treated at 50 and 57 days of age with 2.5 mg per 100 g body weight of N-methyl-N-nitrosourea (MNU). At 60 days of age, the animals were divided into eight groups (40 rats/group) and treated as follows: (a) controls; (b) immune stimulation (IS); (c) hormone inhibition (HI); (d) HI + IS; (e) retinyl acetate feeding (RA); (f) RA + IS; (g) RA + HI; and (h) RA + HI + IS. IS treatment was accomplished by three i.p. injections (at 1, 3, and 5 weeks after carcinogen treatment) of a mixture of cell particulate preparations from pooled MNU-induced rat mammary carcinomas and Freund's (complete) adjuvant. HI treatment consisted of daily s.c. injections of tamoxifen (12.5 to 25.0 micrograms/100 g body weight) and CB-154 (200 to 400 micrograms/100 g body weight), and RA treatment consisted of daily feeding of retinyl acetate (1.0 mM). Both RA alone and HI alone significantly (p less than 0.01 to 0.001) reduced mammary carcinoma incidence; HI treatment was significantly (p less than 0.01) more effective than RA treatment. The combination of RA + HI was significantly (p less than 0.01) superior to either treatment alone; RA + HI treatment virtually completely blocked the development of mammary carcinomas at termination of study (a total of only 2 mammary carcinomas was observed in the RA + HI groups of rats at 1 year after carcinogen treatment). IS treatments did not significantly influence mammary carcinoma incidence, either alone or in combination with RA and/or HI. Female Sprague-Dawley rats given MNU and subsequently treated daily for 4 weeks with the prolactin secretion-stimulating drug haloperidol (0.05 mg/100 g body weight) responded with a significant (p less than 0.001) increase in mammary carcinoma development when compared with control rats. RA treatment of haloperidol-treated rats significantly (p less than 0.001) blocked the stimulatory effect of haloperidol on mammary carcinoma development. The addition of insulin (5.0 micrograms/ml) to the culture media of 2-day organ cultures of MNU-induced rat mammary carcinomas resulted in a significant (p less than 0.05) stimulation of [3H] thymidine incorporation into DNA of the cultured cells.(ABSTRACT TRUNCATED AT 400 WORDS)
59 patients with keratinisation diseases have been received RO 10 9359. There is a clinical medicum tolerance. Biologic controls have been carried out before and after a 3 month treatment. There is a good biological tolerance for the hematopoietic, glucidic, renal and thyroid functions. Thus the hepatic tolerance is poor for the patients with a predisposition for hepatic diseases (plethorics, alcoholics).
Retinoic acid (RA) is able to respecify the positional identity of a regenerating urodele amphibian limb. The regenerate arises from a mesenchymal growth zone or blastema, composed of mesenchymal progenitor cells. Is RA an endogenous ligand and does it act to respecify axial identity? Two recent lines of evidence in favour of an endogenous role are the activation of an RA reporter gene after transfection into the blastema, and the demonstration that the wound epidermis at the end of the regenerate is a source of RA. To analyse the mechanism of action at the receptor level, we have constructed chimaeric newt RA receptor/Xenopus thyroid hormone receptor molecules that allow a single RA receptor to be activated by thyroid hormone.
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Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARbeta2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARbeta2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARbeta2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16.
Since their introduction 15 years ago, retinoids have been increasingly used for topical and systemic treatment of psoriasis and other hyperkeratotic and parakeratotic skin disorders, keratotic genodermatoses, severe acne and acne-related dermatoses, and also for therapy and/or chemoprevention of skin cancer and other neoplasia. Oxidative metabolites of vitamin A (retinol) are natural retinoids present at low levels in the peripheral blood. Synthetic retinoids are classified into 3 generations including nonaromatic, monoaromatic and polyaromatic compounds. They are detectable in plasma 30-60 minutes after systemic administration, and reach maximum concentrations 2 to 4 hours later. Elimination half-life is 10 to 20 hours for isotretinoin, 80 to 175 days for etretinate and 2 to 4 days for, trans-acitretin; the latter, however, partially converts into etretinate. Retinoid concentrations in skin are rather low in contrast to subcutaneous fat tissue. Intracellularly, retinoids interact with cytosolic proteins and specific nuclear receptors. Two classes of nuclear receptors have been suggested to mediate retinoid activity at the molecular level, RARs and RXRs. The expression of retinoid receptors is tissue specific; skin mainly espresses RAR gamma and RXR alpha. Retinoids affect epidermal cell growth and differentiation as well as sebaceous gland activity and exhibit immunomodulatory and anti-inflammatory properties. Current retinoid research targets the development of receptor-selective retinoids for tailoring and/or improving their therapeutic profile. Currently, tretinoin is used systemically for acute promyelocytic leukaemia, etretinate and acitretin for psoriasis and related disorders, as well as other disorders of keratinisation and isotretinoin for seborrhoea, severe acne, rosacea and acneiform dermatoses. Systemic retinoids are also applied for chemoprevention of epithelial skin cancer and cutaneous T cell lymphoma. The major adverse effect of retinoids is teratogenicity; all other adverse effects are dose-dependent and controllable. Contraception is, therefore, essential during retinoid treatment in women of child-bearing age. Clinical monitoring requires physical examination for adverse effects every 3 to 4 weeks and proper laboratory investigations, also including analysis of retinoid bioavailability in selected cases. Topical retinoids are rapidly developing at present and seem promising for the future; their clinical application includes acne, aging, photodamage, precanceroses, skin cancer and disorders of skin pigmentation. The development of receptor-specific retinoids for topical treatment of psoriasis and/or acne may lead to interesting new compounds based on our current concepts of retinoid function.
Retinoids are promising agents for cancer chemoprevention. The myriad effects of retinoids on biological processes including development, differentiation, homeostasis, carcinogenesis and apoptosis are mediated through their molecular targets, the retinoid and rexinoid receptors. Tissue specific expression patterns, ligand specificities, receptor numbers, their distinct functions and functional redundancy make retinoid signaling highly complex. The cross-talks of these receptors with cell surface receptors signaling pathways, as well as their interactions with multiple co-activators and co-repressors further add to the complexity of the pleiotropic effects of retinoids. Elucidation of retinoid signaling pathways and indepth understanding of the mechanisms that underlie the anti-proliferative and apoptotic action of retinoids has paved the way for designing synthetic retinoids for effective chemoprevention and therapy of cancer. Development of receptor selective synthetic retinoids is a major focus of molecular retinoid development. Other new avenues encompass identification of novel retinoid regulated genes, orphan-receptor ligands/functions, novel retinoid mechanisms involving receptor-independent apoptosis inducing activity and synergistic combinations with other agents for cancer prevention and therapy. This review focuses on recent advances in the understanding of molecular mechanisms underlying the action of retinoids and retinoid molecular targeting studies designed primarily to develop retinoids with reduced toxicity, while maintaining or enhancing activity in context of chemoprevention. The clinical efficacy of retinoid based chemoprevention trials is discussed.
The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.
Retinoids are compounds with pleiotropic functions and a relatively selective targeting of certain skin structures. They are vitamins, because retinol (vitamin A) is not synthesized in the body and must be derived from diet, but also hormones with intracrine activity, because retinol is transformed into molecules that bind to nuclear receptors, exhibit their activity, and are subsequently inactivated. Retinoids exert their effects on target cells by binding and activating nuclear retinoid receptors. Retinoid receptors bind their ligands in form of dimers. Heterodimers can be formed between two different retinoid receptor molecules but also between retinoid X receptors and the vitamin D receptor as well as the triiodothyronin receptor. This fact indicates complex interactions between retinoids and further hormonal signal transduction molecules. Interaction of retinoid receptors with transcriptional factors activated by other signal transduction mechanisms, e.g. AP-1, may provide dissociation of the retinoid effects. Retinoids can exhibit agonistic activity but also be neutral antagonists and inverse agonists. Topical and oral retinol, tretinoin, isotretinoin, and bexarotene, topical alitretinoin, retinaldehyde, motretinide, adapalene, tazarotene, and systemin acitretin compose the list of launched retinoids. Psoriasis and related disorders, congenital disorders of keratinization, acne, photoaging and hypovitaminosis A are classical approved indications of retinoid treatment, whereas cutaneous T-cell lymphoma, AIDS-associated Kaposi's sarcoma, acute promyelocytic leukemia and actinic lentigines were currently confirmed. In addition, retinoids have been successfully used in several other dermatoses, e.g. epithelial precanceroses and tumors, seborrhea, rosacea and acneiform dermatoses, lichen planus, eosinophilic folliculitis, condylomata accuminata, lichen sclerosus and atrophicus. Highly receptor selective molecules, retinoic acid receptor-beta-inducers, AP-1 complex antagonists, and inverse agonists will be probably lead the retinoid development in the near future. New, more effective and less toxic retinoids, alone or in combination with other drugs and new delivery systems may provide therapeutic solutions for benign and malignant proliferative skin diseases, such as psoriasis and non-melanoma tumors, cancer chemoprevention and differentiation therapy.
The retinoids are natural and synthetic derivatives of vitamin A. These cancer therapeutic and chemopreventive agents exert anti-proliferative, differentiation-inducing, pro-apoptotic and other biological effects. The retinoids act through nuclear retinoid receptors to activate target genes that signal retinoid biological effects. Direct retinoid targets contain retinoid responsive elements in their promoters, are directly regulated by retinoids and reproduce retinoid biological effects once introduced into a responsive cell context. Through studies conducted in in vitro models, a proteolytic mechanism was linked to retinoid induced tumor cell differentiation and chemopreventive effects. Retinoid treatments can activate the proteasome-dependent degradation pathway. In acute promyelocytic leukemia (APL), all-trans-retinoic acid (RA) can also trigger degradation of the oncogenic protein, PML-RARalpha. Microarray analysis revealed involvement of an E1-like ubiquitin-activating enzyme, UBE1L, in this induction. Retinoid chemopreventive activity in human bronchial epithelial cells was linked to triggering of G(1) cell cycle arrest, concomitant growth suppression, and a decline in expression of G(1) cyclins. This can engage proteasome-dependent cyclin degradation, causing G(1) arrest and this permits repair of genomic DNA damage. The epidermal growth factor receptor (EGFR) was also identified as a retinoid target. Retinoids exert diverse biological effects. Different retinoid target genes likely trigger distinct effects. Identification of target genes is the next step towards a molecular understanding of mechanisms of retinoid response or resistance in cancer therapy and chemoprevention.
Acyclic retinoid (polyprenoic acid) has a slightly different structure from retinoic acid. However, acyclic retinoid acts similarly to retinoic acid, because both bind to cellular retinoic acid-binding protein and cellular retinoid-binding protein. F-type, with the same strong binding affinity. We studied the effects of acyclic retinoid, the 7-hydroxy derivative of acyclic retinoid (7OH-acyclic retinoid) and retinoic acid on a human hepatoma-derived cell line PLC/PRF/5 (Alexander cells). Acyclic retinoid inhibited cell growth with an ID50 value of 14 microM, and reduced cell viability with an LD50 value of 86 microM. The ratios of LD50 value to ID50 value were 6.1 for acyclic retinoid, 2.4 for 7OH-acyclic retinoid and 1.4 for all-trans-retinoic acid. Taking this ratio as a parameter of relative cytotoxicity, we concluded that acyclic retinoid is the least toxic compound. Growth inhibition of cells by acyclic retinoid was associated with the incorporation of 3H-thymidine in the logarithmic phase. Acyclic retinoid reduced secretion of alpha-fetoprotein (AFP) and reciprocally increased secretion of albumin in the culture media, suggesting that acyclic retinoid influences gene expression of these proteins. Thus, acyclic retinoid, one of the less toxic retinoids, inhibits cell growth of human cancer cell line PLC/PRF/5 and appears to alter gene expression of AFP and albumin toward a "normal" direction.
Retinoids are effective inhibitors of chemical carcinogenesis in the skin, mammary gland, esophagus, respiratory tract, pancreas, and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with enhanced target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Newer retinoidal benzoic acid derivatives are even more active. Combining retinoid treatment with other modulators of carcinogenesis results in a synergistic inhibition of tumor development. Retinoids in combination with hormonal manipulation are much more effective in inhibiting mammary carcinogenesis than is either treatment alone; this combination approach also inhibits mammary tumor recurrence following surgical removal of the first tumor. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment is delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods. The mechanism(s) by which retinoids inhibit carcinogenesis is unknown; however, in the mammary gland, retinoids inhibit differentiation and proliferation, DNA synthesis, and RNA polymerase activity. Cytosolic retinoid-retinoid receptor complexing is apparently a prerequisite for the nuclear interaction of retinoids, at least in mammary cells.
BACKGROUND: Retinoic acid analogues, called retinoids, have shown promise in clinical trials in preventing breast and ovarian cancers. Classic retinoids bind to retinoic acid receptors, which regulate cell growth. Some novel retinoids, such as fenretinide, i.e., N-(4-hydroxyphenyl)retinamide (4-HPR), induce apoptosis through retinoic acid receptor-independent mechanisms; however, they appear to do so only at concentrations above those achieved in clinical chemoprevention trials. At lower concentrations (< or =1 microM), 4-HPR acts like classic retinoids, by inducing differentiation through a receptor-dependent mechanism. Our goal was to compare the effects of novel receptor-independent (apoptotic) retinoids with those of classic growth-inhibitory retinoids at clinically achievable doses on growth, differentiation, and apoptosis in ovarian tissue. METHODS: Four receptor-independent (apoptotic) and seven growth-inhibitory retinoids, including synthetic, low-toxicity compounds called heteroarotinoids, were administered at concentrations of 1 microM to organotypic cultures of ovarian primary and cancer cell lines: OVCAR-3, Caov-3, and SK-OV-3. After fixation, embedding, and sectioning, the growth fraction was quantified by measuring expression of the proliferation marker Ki-67/myb, differentiation was assessed by expression of mucin, and apoptosis was evaluated by the TUNEL assay. Spearman correlation analysis was performed on the data, and all P values were two-sided. RESULTS: All 11 retinoids reversed characteristics associated with the cancerous phenotype in all neoplastic cultures. Glandular structures were observed consistently in retinoid-treated, but not in untreated, OVCAR-3 and Caov-3 cultures. All retinoids decreased growth fractions, and some increased mucin expression. All receptor-independent retinoids and two receptor-dependent retinoids induced apoptosis, and the induction correlated significantly with increased expression of the mucin MUC1 (r =.83; P =.03). Retinoids with ester-linking groups did not induce apoptosis but decreased the growth fraction in correlation with MUC1 induction (r = -.93; P =.02). CONCLUSIONS: At clinically achievable concentrations, all retinoids tested decrease the growth fraction, induce differentiation and apoptosis. Induction of MUC1 expression is implicated in the mechanisms of action.
Retinoids are known to inhibit the growth of a wide variety of cancer cells, including breast cancer cells. Advances made in recent years in the understanding of the molecular mechanisms of retinoid action have allowed the design of retinoids with selective activities. Such selective retinoids are of particular interest, because they may reduce the number of undesirable side effects observed with natural compounds. Here, we have compared the growth-inhibitory activities of natural retinoids with various selective retinoids, including anti-activator protein (AP)-1 selective compounds on estrogen receptor-positive and -negative breast cancer cell lines. In addition, we have investigated cooperativity between selective retinoids and IFNs and have begun to analyze the pathways that these two different growth inhibitors use for antagonizing breast cancer cell proliferation. We observe that several selective retinoids can inhibit breast cancer cells as efficiently as the natural compounds. Anti-AP-1-selective retinoids are as effective as retinoic acid receptor (RAR)-beta/gamma-selective compounds. This lets us conclude that retinoid-induced inhibition of breast cancer cell growth does not require retinoid receptor transactivation. Several synthetic retinoids including anti-AP-1-selective compounds show synergism with IFNs. However, true synergism between the two different types of growth regulators was seen only when both classes of molecules were used at low concentrations. RAR-beta/gamma and anti-AP-1-selective retinoids, but not RAR-alpha-selective compounds, induced increased RAR-gamma mRNA levels. Interestingly, IFNs at elevated concentrations (100 units/ml and higher) also induced increased RAR-gamma expression. Thus, when used at high concentrations, IFNs may activate growth-inhibitory pathways overlapping with those activated by retinoids. Because increased RAR-gamma expression is induced by the two different classes of breast cancer cell inhibitors, it is likely to have an important role in controlling the growth fo these cancer cells.
Body retinoids are stored in the lipid droplets of hepatic stellate (Ito) cells. In chronic liver disease, the stellate cells differentiate into myofibroblast-like cells, a process whereby they lose their retinoid-containing lipid droplets. We studied the relation between liver retinoid content, the number of lipid droplets per stellate cell, and the number of stellate cells per mm2 in human alcoholic liver disease. Semithin sections of liver biopsies from normal subjects and patients with early (steatosis, inflammation, and mild fibrosis) and late (cirrhosis and cirrhosis with acute alcoholic hepatitis) alcoholic liver disease were morphometrically evaluated. Liver retinoid content was determined by HPLC. In normal patients, liver retinoid content was 901 +/- 213 IU/g of liver (mean +/- SEM). There was a decrease in liver retinoid content in early alcoholic liver disease (409 +/- 50 IU/g) and a further reduction in cirrhosis (153 +/- 50 IU/g). In patients with acute alcoholic hepatitis, retinoid content was strikingly low (5.2 +/- 1.8 IU/g). There was a progressive decrease in the number of stellate cells per mm2 associated with progressive liver damage. We found a fair correlation between the number of stellate cells per mm2 and liver retinoid content in all patient groups (overall correlation: 0.71). In normal subjects, the mean number of lipid droplets per stellate cell was 7.4 +/- 0.7. In patients with early alcoholic liver disease and in patients with alcoholic cirrhosis, this value was increased to 13.6 +/- 0.8 and 10.4 +/- 2.0, respectively. In patients with acute alcoholic hepatitis, only a few lipid droplets were present (4.2 +/- 0.5). There was a good correlation between liver retinoid content and mean number of lipid droplets in normal patients (r = 0.58). In alcoholic cirrhosis, however, correlation was poor (r = 0.34). In early alcoholic liver disease, the correlation was absent (r = 0.004). In conclusion, the major finding of our study is that the correlation between the mean number of lipid droplets per stellate cell and liver retinoid content varies according to the hepatic pathology considered. Marked lipid droplet accumulation occurs in stellate cells in early alcoholic liver disease and, to a lesser extent, in alcoholic cirrhosis, but there is no correlation between the mean number of lipid droplets per stellate cell and liver retinoid content. Therefore, not retinoids but probably lipids are responsible for the accumulation of lipid droplets. We also find that there is a fair correlation between the number of stellate cells per mm2 and liver retinoid content in all patient groups. Finally, we confirm the decrease in hepatic retinoid content that occurs in alcoholic liver disease in humans, even at the early stages of the disease.
Retinoids have been used in the clinic for the prevention and treatment of human cancers. They regulate several cellular processes including growth, differentiation, and apoptosis. Previously, we demonstrated that a pan-agonist retinoid 9-cis retinoic acid was able to suppress mammary tumorigenesis in the C3(1)-SV40 T-antigen (Tag) transgenic mouse model. However, significant toxicity was seen with this naturally occurring retinoid. We hypothesized that the cancer preventive effects of retinoids could be dissected from the toxic effects by using receptor-selective retinoids. In this study, we used TTNPB, an retinoic acid receptor-selective retinoid, and LGD1069, an retinoid X receptor-selective retinoid, to preferentially activate retinoic acid receptors and retinoid X receptors. In vitro, both compounds were able to inhibit the growth of T47D breast cancer cells. We then determined whether these retinoids prevented mammary tumorigenesis. C3(1)-SV40 Tag mice were treated daily by gastric gavage with vehicle, two different doses of TTNPB (0.3 or 3.0 microg/kg), or two different doses of LGD1069 (10 or 100 mg/kg). Mice were treated from approximately 6-8 weeks to 7-8 months of age. Tumor size and number were measured twice each week, and toxicities were recorded daily. Our data show that LGD1069 suppresses mammary tumorigenesis in C3(1)-SV40 Tag transgenic mice with no observable toxicity, whereas TTNPB had a modest chemopreventive effect, yet was very toxic. Median time to tumor development was 129 days in vehicle-treated mice versus 156 days in mice treated with 100 mg/kg LGD1069 (P = 0.05). In addition, tumor multiplicity was reduced by approximately 50% in mice treated with LGD1069 (2.9 for vehicle, 2.4 for 10 mg/kg LGD1069, and 1.4 for 100 mg/kg, P < or = 0.03). TTNPB-treated mice showed a delayed median time to tumor development (131 days for vehicle versus 154 days for 3.0 microg/kg TTNPB; P < or = 0.05), but no changes were seen in tumor multiplicity. However, toxicity (skin erythema, hair loss) was seen in all of the mice treated with TTNPB. These data demonstrate that receptor-selective retinoids suppress mammary tumorigenesis in transgenic mice and that preventive effects of retinoids can be separated from their toxicity, demonstrating that receptor-selective retinoids are promising agents for the prevention of breast cancer.
OBJECTIVE: Retinoids are known to exhibit a broad spectrum of biological activities, and they participate in the onset of differentiation and the inhibition of growth in a wide variety of cancer cells. Some of these vitamin A derivatives are already in clinical use. However, data on retinoid actions in glial tumors are rather sparse. Therefore, we studied the effects of the natural retinoic acid (RA) forms all-trans-RA, 9-cis-RA, and 13-cis-RA on glioma cell lines and primary cultures from patients with glioblastomas multiforme. METHODS: Six human glioma cell lines, one rat glioma cell line, and 20 primary cultures established from biopsies from patients with glioblastomas multiforme were investigated. Tumor cell proliferation was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and cell-counting assays. Random migration out of tumor spheroids was quantified using a video-morphometry system. Invasion was investigated using a confrontational coculture test system. Retinoid receptor (RA receptor [RAR]alpha, -beta, and -gamma and retinoid X receptor [RXR]alpha, -beta, and -gamma) expression status was determined using reverse transcription-polymerase chain reaction studies. RESULTS: Treatment of five human glioma cell lines with the different retinoids at concentrations up to 10(-5) mol/L produced no reduction of proliferation, using various incubation times. For one human glioma cell line (U343MG-A) and one rat glioma cell line (C6), which were previously reported to be sensitive to retinoids, we could confirm strong inhibitory effects on proliferation and clear changes in morphological features after retinoid treatment. Application of the different retinoids to low-passage primary cultures of human glioblastomas resulted in marked inhibition of proliferation (30-95%) for all tested samples. Using three-dimensional spheroid cultures, we detected retinoid-induced decreases in cell migration (24-65%). Invasion was not affected by these vitamin A derivatives. In an analysis of the expression patterns for retinoid receptors (RARs and RXRs), all primary culture samples yielded positive results for RAR gamma and RXR alpha and negative results for RAR alpha, RAR beta, and RXR gamma, whereas the results of RXR beta expression were heterogeneous among different patients. The cell lines, irrespective of their RA sensitivities, did not exhibit any major differences in receptor expression. CONCLUSION: Retinoids strongly inhibit proliferation and migration in primary cultures of human glioblastomas multiforme. Our data support a clinical trial of retinoids for the treatment of human malignant gliomas. We observed that most established cell lines were not sensitive to RA. This difference between long-term cell lines and primary cultures cannot be explained by different retinoid receptor expression patterns.