Plasma retinoid levels in head and neck cancer patients: a comparison with healthy controls and the eect of retinyl palmitate treatment M.P. Copper a , I. Klaassen a , T. Teerlink b , G.B. Snow a , B.J.M. Braakhuis a, * a Department of Otolaryngology/Head and Neck Surgery, University Hospital Vrije Universiteit, Amsterdam, Netherlands b Department of Clinical Chemistry, University Hospital Vrije Universiteit, Amsterdam, Netherlands Received for publication 28 July 1998 Abstract Vitamin A and related compounds, also known as retinoids are thought to play a role in the development of head and neck cancer. We measured levels of the major retinoids, retinol, all-trans retinoic acid, 13-cis retinoic acid and 13-cis-4-oxo retinoic acid in plasma of head and neck cancer patients in comparison with controls without cancer. No dierences were found between plasma levels of these retinoids between 25 head and neck cancer patients and 21 controls. Mean baseline levels for the patients were 2458, 6.0, 6.4 and 8.6 nM for retinol, all-trans retinoic acid, 13-cis retinoic acid and 13-cis-4-oxo retinoic acid, respectively. In addition, we selected 10 patients from the chemoprevention trial Euroscan and measured the eect on retinoid levels of 300,000 I.U. daily retinyl palmitate intake during 1 month. Medication caused signi®cant elevations in retinol levels (1.2 fold), all-trans retinoic acid (2.2 fold) and its metabolites 13-cis retinoic acid (5.8 fold) and 13-cis-4-oxo retinoic acid (8.9 fold). Because of its high increase in levels, 13-cis-4-oxo retinoic acid seems a good candidate to serve as a suitable marker to monitor patient compliance in future chemo- prevention trials involving retinoids. No relations were found between the occurrence of side-eects of retinyl palmitate and reti- noid levels during treatment. However, the two patients who developed side-eects had the highest pre-treatment levels of 13-cis retinoic acid and 13-cis-4-oxo retinoic acid, suggesting that retinoid toxicity is associated with relatively high basal retinoid meta- bolism. # 1998 Elsevier Science Ltd. All rights reserved. Keywords: 13-cis-4-oxo Retinoid acid; 13-cis Retinoic acid; all-trans Retinoic acid; Chemoprevention; Euroscan; Retinoids; Retinyl palmitate; Squamous cell carcinoma; Vitamin A 1. Introduction Vitamin A or retinol is an essential micronutrient for several processes in man including growth, dierentia- tion, vision and reproduction. The relation between dietary intake of retinol and the development of squa- mous cell cancer in several tissues of the body was recognized during the last two decades [1±3]. Epide- miological studies on the relation between low serum concentrations of retinol and subsequent cancer risk were not conclusive. A number of these studies showed a positive correlation between low serum retinol con- centrations and the development of cancer [4,5], but other studies failed to con®rm this [6±9]. From the clin- ical point of view it was recognized that vitamin A has activity in leukoplakia, the most common premalignant form of oral cancer. Oral suppletion of retinoic acid (RA) in the form of 13-cis RA was also able to prevent the formation of second primary tumors in head and neck cancer patients [10]. At this moment it is not clear how retinol and its metabolites (termed `retinoids') are able to inhibit the development of cancer. It is very likely that in addition to the availability of retinoid receptors (discussed below), the concentrations of the speci®c retinoids are important [11]. Many studies in the past have put emphasis on serum retinol levels and the subsequent risk of cancer development, but not much is known about normal plasma levels of all-trans RA and its metabolites 13-cis RA and 13-cis-4-oxo RA in cancer patients. The ®rst aim of this study was to analyze these retinoids in the plasma of head and neck cancer patients in comparison with controls. In the late 1980s more insight into the molecular mechanisms of the action of vitamin A was acquired by the discovery of the RA receptors (RARs) and the retinoid X receptors (RXRs) ORAL ONCOLOGY Oral Oncology 35 (1999) 40±44 1368-8375/98/$Ðsee front matter # 1998 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(98)00084-0 * Corresponding author. Tel. +31-20-4440905; fax: +31-20- 4440983; e-mail: bjm.braakhuis@azvu.nl