Differentiation, retinoid induced

Vitamin A derivative (retinoid) induces differentiation, maturation of immature promyelocytic cells... 

Retinoids failed to activate NADPH oxidase in dibutyryl cAMP differentiated HL-60 cells (Seifert and SCHACHTELE 1988). In HL-60 cells retinoids have been found to potentiate formyl-methionyl-leucyl-phenylalanine-induced and phorbol myrist-ate acetate-induced 02 formation (Seifert and SchAchtele 1988). Using receptor specific retinoid analogues it was demonstrated that retinoid X receptor-retinoic acid receptor heterodimers mediate retinoid-induced differentiation of HL60 cells, while retinoid X receptor-retinoid X receptor homodimers mediate subsequent retinoid-mediated apoptosis (Nagy et al. 1995, Kizaki et al. 1996). 

Peck R, Bollag W (1991) Potentiation of retinoid-induced differentiation of HL-60 and U937 cell lines by cytokines. Eur J Cancer 27 53-57... 

The specific role of vitamin A in tissue differentiation has been an active area of research. The current thinking, developed in 1979, involves initial dehvery of retinol by holo-B >V (retinol-binding protein) to the cell cytosol (66). Retinol is then ultimately oxidized to retinoic acid and binds to a specific cellular retinoid-binding protein and is transported to the nucleus. Retinoic acid is then transferred to a nuclear retinoic acid receptor (RAR), which enhances the expression of a specific region of the genome. Transcription occurs and new proteins appear during the retinoic acid-induced differentiation of cells (56). 

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

There has been some concern expressed regarding the use of CSFs to treat MDS patients. Because these cytokines have proliferative activity, they have the potential to induce a leukaemic transformation in the malignant clone. However, the combined use of CSFs with cytotoxic drugs such as cytosine arabinoside (ara-C) appears promising. If leukaemic clones are induced to proliferate by the cytokine, then they are killed by ara-C as they enter the cell cycle. Other forms of differentiation therapy, such as treatment with retinoids, 1,25-dihydroxyvitamin D3 and interferons, have also been tested, but results have been variable. 

Mechanism of Action A retinoid that decreases cohesiveness of follicular epithelial cells. Increases turnover of follicular epithelial cells. Bacterial skin counts are not altered. Transdermal Exerts its effects on growth and differentiation of epithelial cells. Antineoplastic Induces maturation, decreases proliferation of acute promyelocytic leukemia (APL) cells. Therapeutic Effect Causes expulsion of blackheads alleviates fine wrinkles, hyperpigmentation causes repopulation of bone marrow and blood by normal hematopoietic cells. 

Oxoretinol induces differentiation of cells in culture (Achkar et td., 1996). In the developing Xenopus embryo, 4-oxoretinaldehyde is the major retinoid, acting tis a precursor of both 4-oxoretinol and 4-oxoretinoic acid, both of which activate the RAR (Blumberg et al., 1996). This developmented role of... 

Retinoic acid, an endogenous retinoid, is a potent inducer of cellular differentiation. Because cancer is fundamentally a loss of cellular differentiation, circulating levels of retinoic acid could play an important role in chemoprevention. However, physiological concentrations are typically below the limits of HPLC detection. Sensitive techniques, such as negative chemical ionization (NCI) GC/MS have been employed for quantification, but cause isomerization and also fail to resolve the cis and trans isomers of retinoic acid. Normal phase HPLC can resolve the cis and trans isomers of retinoic acid without isomerization, and mobile phase volatility makes it readily compatible with the mass spectrometer. Based on these considerations, a method combining microbore normal phase HPLC separation with NCI-MS detection was developed to quantify endogenous 13-cis and all-trans retinoic acid in human plasma. The limit of detection was 0.5 ng/ml, injecting only 8 pg of retinoic acid onto the column. The concentration of 13-cis retinoic acid in normal, fasted, human plasma (n=13) was 1.6 +/- 0.40 ng/ml. 

Retinoic acid, an endogenous retinoid, is an oxidized metabolite of retinol (vitamin A), and the most potent known inducer of differentiation in vitro (17-191. It is, therefore, most likely the form of vitamin A which promotes normal cellular differentiation. Because cancer is fundamentally a loss of cellular differentiation, physiological concentrations of retinoic acid may play an important role in the etiology of cancer. 

Bexarotene is a retinoid that binds and activates retinoid X receptor subtypes (RXRot, RXRp, RXRy). Once activated, these receptors function as transaiption factors that regulate the expression of genes that control cellular differentiation and proliferation, inhibit the growth in vitro of some tumor cell lines of hanatopoietic and squamous cell origin, and induce tumor regression in vivo in some animal models. Bexarotene is indicated in refractory cutaneous T-ceU lymphoma. 

A hallmark of malignant transformation is a block in differentiation. A number of chemical entities, including vitamin D and its analogs, retinoids, benzamides and other inhibitors of histone deacety-lase, various cytotoxics and biological agents, and inhibitors of DNA methylation, can induce differentiation in tumor cell lines. 

In addition to growth inhibition and apoptosis, retinoids are well-established as redifferentiating agents in vitro. Redifferentiation and growth inhibition have been documented in osteosarcoma cell lines in vitro (Barroga et al, 1999). In human myeloid leukemia cell lines, all-tra wr-RA can induce differentiation to granulocytic- or monocytic-like cells. The same effect can be demonstrated in leukemic cells from patients with promyelocytic leukemia (Chomienne ij /., 1990). 

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