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This volume contains papers presented at the Conference on Retinoids: New Trends in Research and Clinical Applications, held in 1991 in Palermo, Italy, describing the latest research findings on biochemistry, nutrition, molecular and cell biology and developmental biology, as well as the pharmacology and the therapeutic use of vitamin A and its congeners.;Written by leading authorities in the field from the USA, Europe and Japan, Retinoids, amongst other things: addresses retinol-supported retinoic acid (RA) synthesis and catabolism; identifies synthetic ligands with a high selective affinity for RAR-alpha, -beta and -gamma nuclear receptors, determining if they would show pharmacological properties similar to the natural parent substance all-trans RA; considers the embryonic/foetal cellular retinoid-binding proteins and evidence for their participation in normal and abnormal morphogenesis; discusses a novel arotinoid, Ro 40-8757, that exhibited improved anti-tumour efficacy and safety in pre-clinical tests; and reports the audioradiographic distribution of retinol and RA in organs of pregnant hamsters and foetuses.
With the aromatic retinoic acid analog Tigason oral and intravenous pharmacokinetic studies have been performed in 5 normal volunteers. Simultaneous fitting of single i. v. and oral data to a three-compartment model assuming first-order absorption was possible. Using Nonlin parameter estimates of the single-dose data, one is able to predict the decline in plasma levels of parent drug following cessation of a 10 days multiple dosing regimen up to 24 hours. The model is however unable to predict a phase of prolonged elimination observed beyond 24 hours. Moreover in 5 patients, who underwent chronic therapy (8-15 months), substantial plasma levels of both unchanged drug and main metabolite (corre sponding carboxylic acid) were observed up to 140 days after cessation of the therapy. An apparent half-life of elimination of 80-100 days can be calculated. The drug appears to be stored at some yet unknown storage site. Investigation of metabolism of Tigason in rats and humans revealed 19 different bio transformation products thus far, most of them appearing in the urine in low amounts (20010 of dose). A few of them (mainly the acid Ro 10-1670) after conjugation to glucuronic acid are excreted in the bile in high amounts (60-80% of dose). No drug appeared unchanged in the excreta after i. v. administration to rats. References 1. Bollag W (1971) Effects of vitamin A acid (NSC-122758) on transplantable and chemically-induced tumors. Cancer Chemother Rep 55:53-58 2.
Recent developments with respect to the biology and clinical use of retinoids in cancer therapy and prevention are comprehensively covered by experts in this new field. Newer aspects of molecular mechanisms of retinoid effects, the cellular biology and the developmental effects of these compounds are presented together with a comprehensive description of the latest findings of retinoid pharmacology, toxicology and clinical effects in a wide range of hematological and solid malignancies.
Retinoids have received considerable attention in recent years and due cognizance has been given to their versatility as biological response modifiers, as evidenced by the virtually explosive growth of literature in this field in the past few years. This volume has been designed to give a current state-of-the-art picture of retinoids. The perceived potential of retinoids in the treatment of certain disease stated has initiated attempts at identifying and synthesizing new retinoid derivatives with definable and selective effects on aberrant biological phenomena. Appropriately, therefore, we begin with the chemistry of retinoids and their derivatives together with discussions of their biological activity. Major advances have been made in understanding the mechanisms by which retinoids modulate physiological and phenotypic traits of cells. The transduction of retinoid signaling by the mediation of nuclear receptors of the steroid/thyroid receptor superfamily has now been studied extensively and the cloning and defining the characteristics of these receptors has been a focus of discussion in this volume. Retinoids also markedly modulate the transduction of extracellular signals such as those imparted by growth factors and hormones, and thus actively influence and control cellular proliferative patterns. Retinoids can alter epidermal growth factor receptor expression (Kawaguchi et al., 1994), responsiveness to thyroid hormone (Esfandiari et al., 1994; Pallet et al., 1994), inhibit the proliferative responses of hematopoietic progenitor cells to granulocyte colony stimulating factor (Smeland et al., 1994), and modulate secretion on interleukins by leukaemic cells (Balitrand et al., 1994), among other things. This has obvious implications for pharmacological manipulation of deregulated growth (Dickens and Colletta, 1993; Mulshine et al., 1993). Apoptosis is another component in the regulation of growth control. Apoptotic cell death is influenced by several agents and retinoids may function by interfering with apoptotic pathways of regulation of growth control and quite legitimately, therefore, the importance of this aspect of retinoid function has been duly recognized here.
The purpose of this book is to present an overview of advances in both retinal and retinoic acid synthetic chemistry and biology. Chapters are written by research workers who are active in these fields. Emphasis is placed on structure-activity relationships. It includes topics of cell differentiation, maintenance of cell morphology, and vision. This reference contains a special section on assays which were developed to measure retinoid activity. This book is ideal for those interested in the fields of photobiology, organic chemistry, biological chemistry, and nutrition.
First multi-year cumulation covers six years: 1965-70.

Retinoids

IARC Working Group on the Evaluation of Cancer-preventive Agents

Published: 1999

Total Pages: 360


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The impact of the retinoids in clinical practice has primarily been in dermatology. When Dr Werner Bollag began his basic research and screening programme in the early 1960's, the expectation was that the retinoids would have a major impact on oncology. However, the laboratory and clinical experiences of Bollag and his colleagues in Switzerland, Stuttgen and Orfanos in Germany, led to publications on both etretinates (Tigason) and isotretinoin (Roaccutane) in the years between 1972 and 1976 in the field of dermatology. In fact the first symposium on retinoid research held in Berlin in 1981 was almost entirely dermatological. A year later a retinoid workshop in Iowa was designed to provide a forum for dermatolog ists from the USA involved in specific protocols investigating oral retinoids. In the UK, research into the retinoids began rather later than in Continental Europe or in the USA, although Tigason was first marketed here. It was felt in late 1982 that as many dermatologists had relatively little experience with these compounds it would be appropriate to hold an International Symposium on retinoid therapy in the UK. Thus on 16-18 May 1983 in London, 37 speakers from 11 countries addressed an audience of 300, aminly UK, dermatologists. The scientific organizing committee consisted of but two persons Dr William Cunliffe of Leeds General Infirmary, representing the European Society of Dermatolo gical Research, and myself from Roche Clinical Research. The Symposium was held under the auspices of the ESDR and of Roche Products Limited.