Systems based modelling of retinoid drug interactions

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Interactions among native and synthetic retinoids, other nutrients, and certain hormones and chemopreventive and/or chemotherapeutic agents remain to be delineated. The relationship between these interactions and various carcinogenic processes are even less well characterized. After years of intensive study, the use of retinoids as chemopreventive and/or chemotherapeutic agents has yielded some encouraging results, but overall, results have been mixed. Nevertheless, the critical role of retinoids in normal cellular growth and differentiation processes requires that we better understand basic aspects of retinoid function and interactions independent of any potential chemopreventive and/or chemotherapeutic properties that might be found to be associated with these compounds. Moreover, the potential clinical usefulness of retinoids as chemopreventive and/or chemotherapeutic agents, which arguably has been limited in the past by a lack of understanding of basic aspects of the metabolism and related dynamics of these compounds, is unlikely to be fully realized until a number of basic areas of research in this area are clarified. To accomplish this, we have designed and are conducting a number of complementary in vivo and in vitro studies to examine the mechanisms involved in retinoid-nutrient-drug interactions and their role in cancer. Based on the results of our in vivo studies, we have developed physiologically-based, mathematical/compartmental models to describe the metabolism of retinoids and various retinoid interactions in a number of tissues. For example, our previous work has indicated that the synthetic retinoid 4-HPR interferes with normal uptake and/or metabolism of native retinoids in the eyes, prostate and adrenal gland, as well as a number of other tissues examined. Our findings in the eyes have provided a mechanistic explanation for the visual disturbances often observed in human trials using 4-HPR and moreover, they highlight the practical and clinical applicability of our overall approach. In contrast, administration of all-trans retinoic acid, another retinoid used as a chemopreventive and/or chemotherapeutic agent, was not associated with similar types of perturbations in retinoid kinetics, supporting the notion of retinoid and tissue specific effects associated with administration different types of retinoids. To test the hypotheses derived from our in vivo models and to study in greater detail the mechanisms involved in the alterations of native retinoid dynamics that we observed, we have screened and subsequently modified a number of in vitro systems to mimic physiological responses we have observed in vivo. Thus far, we have carried out studies in a novel tissue culture system for human retinal pigment epithelium as well as in normal and transformed human prostate and mammary cell lines. One focus of the latter work is to characterize perturbations of the normal dynamics of native retinoid following administration of certain retinoid or retinoid:drug combinations, and to relate these changes in dynamics to retinoid related events at the cellular and molecular level. The latter would include alterations in certain enzymatic activities as well as expression of certain retinoid-binding proteins, nuclear retinoid receptors, and transcription factors. Other studies, planned or in progress, will include in vivo turnover studies in normal female animals similar to those we have conducted with males, as well as related studies using mammary tumor models.