RETINOIC ACID THERAPY FOR PROMYELOCYTIC LEUKAEMIA
Christine ChomiennePaola BalleriniN BalitrandMichèle AmarJean BernardPierre BoivinMarie Thérèse DanielRoland BergerSylvie CastaignéLaurent Degos
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Genentech is partnering with the German cancer company Affimed to develop immunotherapies for multiple kinds of solid and blood cancers. Affimed is developing therapies that engage natural killer cells of the innate immune system to help direct them to attack cancer cells. Genentech will pay Affimed $96 million up front and up to $5 billion more in potential payments.
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Factors modulating the effect of retinoids on cultured retinal pigment epithelial cell proliferation
The effect of several naturally-occurring retinoids and 13-cis-retinoic acid on the proliferation of cultured bovine retinal pigment epithelial (RPE) cells was investigated. None of the retinoids tested were toxic to the cultures and all, except retinylpalmitate, inhibited cell proliferation when given for more than 3 days. The relative potencies of the retinoids were; all-trans-retinoic acid > 13-cis-retinoic acid > all-trans-retinol ≅ all-trans-retinaldehyde. Uptake of retinoic acid by cultured RPE cells was 10-fold less than the uptake of retinol. Although retinoic acid-treated cultures showed strong density-dependent growth inhibition, cellular proliferation was inhibited more in sparse cultures than in dense ones. Retinoic acid did not significantly inhibit the proliferation of first passage bovine or rabbit RPE cells, but partially inhibited the proliferation of first passage human RPE cells. The sensitivity of all these cultures to growth inhibition by retinoic acid increased in subsequent subcultures, yet there was no effect of passage number on retinoic acid uptake. This study demonstrates that RPE cell proliferation can be inhibited by retinoic acid but the sensitivity of these cells to the retinoid's effects are modulated by incubation time, in vitro aging, and cell density.
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Retinoic acid (RA) is one of the factors crucial for cell growth, differentiation, and embryogenesis; it interacts with the retinoic acid receptor and retinoic acid X receptor to eventually regulate target gene expression in chordates. RA is transformed from retinaldehyde via oxidization by retinaldehyde dehydrogenase (RALDH), which belongs to the family of oxidoreductases. Several chemicals, including disulphiram, diethylaminobenzaldehyde, and SB-210661, can effectively inhibit RALDH activity, potentially causing reproductive and developmental toxicity. The modes of action can be sequentially explained based on the molecular initiating event toward key events, and finally the adverse outcomes. Adverse outcome pathway (AOP) is a conceptual and theoretical framework that describes the sequential chain of casually liked events at different biological levels from molecular events to adverse effects. In the present review, we discussed a recently registered AOP (AOP297; inhibition of retinaldehyde dehydrogenase leads to population decline) to explain and support the weight of evidence for RALDH inhibition-related developmental toxicity using the existing knowledge.
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Objective: To investigate the mechanism of cleft palate in mice induced by excessive all-trans retinoic acid (atRA). Methods: The pregnant mice were randomly divided into atRA-treated group (n=27) and control group (n=27). atRA-treated group was given by gavage a single dose of atRA (100 mg/kg) at 8: 00 AM on gestation day 10 (GD10) and the control group was given by gavage the isopyknic corn oil. At GD13-GD15, the fetal mice palate development was observed by HE staining. The mouse embryonic palatal mesenchymal cell proliferation was detected by 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry. The expressions of Smad2, phospho-Smad2 (p-Smad2), Smad4 and Smad7 in mouse embryonic palatal mesenchyme were analyzed by Western blotting. Results: At GD13-GD15, compared with the control, the ratio of BrdU-positive cells in the palatal mesenchyme of atRA-treated fetuses decreased significantly (P<0.05), especially at GD14, atRA inhibition rate was (65.4±1.7)%. Moreover, atRA decreased the levels of p-Smad2 and Smad4 in embryonic palate mesenchymal cells, whereas the expression of Smad7 was significantly increased at GD14 and GD15. Conclusions: atRA may lead to cleft palate by inhibiting the activation of Smad signaling pathway and affecting the proliferation of palatal mesenchymal cells.目的： 通过建立小鼠腭裂模型观察全反式维甲酸（all-trans retinoic acid，atRA）对胎鼠腭突间充质细胞增殖及转化生长因子β（transforming growth factor-β，TGF-β）/Smad信号通路的影响，探讨atRA诱发腭裂的机制。 方法： 将孕鼠根据体质量按随机数字表随机分为atRA组和对照组（每组各27只），于妊娠第10天（gestation day 10，GD10）上午8时，分别予以100 mg/kg atRA和等体积玉米油溶剂灌胃。HE染色观察GD13~GD15胎鼠上腭发育，5-溴脱氧尿嘧啶核苷（5-bromo-2-deoxyuridine，BrdU）免疫组织化学染色观察atRA对GD13~GD15胎鼠腭突间充质细胞增殖的影响，蛋白质印迹法检测胎鼠腭突间充质细胞内Smad2、磷酸化Smad2（phospho-Smad2，p-Smad2）、Smad4、Smad7的蛋白表达。 结果： 与对照组相同时间点相比，atRA组GD13~GD15胎鼠腭突间充质细胞BrdU阳性率均显著降低（P<0.05），尤其是GD14，atRA抑制率达（65.4±1.7）%。与对照组相同时间点相比，atRA组GD14和GD15胎鼠腭突间充质细胞p-Smad2和Smad4蛋白表达显著降低（P<0.05），GD13~GD15胎鼠腭突间充质细胞Smad7蛋白表达显著升高（P<0.05）。 结论： atRA可能通过抑制Smad信号通路的激活影响腭突间充质细胞增殖，从而导致腭裂的发生。.
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Retinoic acid has been shown to induce large accumulations of tissue transglutaminase in cultured myeloid cells. Addition of retinoic acid to mouse resident peritoneal macrophages increased the level of tissue transglutaminase mRNA within 30-60 min. Retinoic acid also increased tissue transglutaminase mRNA levels in human promyelocytic leukemia (HL-60) cells. These studies show that retinoic acid can induce acute alterations in specific gene expression in both normal and leukemic myeloid cells.
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Tumor-derived retinoic acid promotes monocyte differentiation into immunosuppressive macrophages.
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Retinoic acid prevents the decrease in epidermal Langerhans' cell (LC) density which occurs upon application of the tumour promotor 12-O-tetradecanoylphorbol 13-acetate (TPA) to murine skin. This occurred very rapidly, after only 1 week, and was still observed after 4 weeks of treatment. Retinoic acid alone increased the LC density, indicating that it could affect LC density independently of TPA. The induction of a contact sensitivity response which was inhibited by prior treatment with TPA due to the low LC density was also protected by retinoic acid. The anti-carcinogenic activity of retinoic acid is partially the result of its ability to inhibit tumour promotion. The loss of LC may be one of the important steps in tumour promotion as this would allow developing tumours to escape immune destruction. Our studies suggest that the ability of retinoic acid to suppress tumour promotion may be in part by protecting local antigen-presenting cells, thus allowing an immune response to be generated against tumours.
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