A systems modeling approach to the study of retinoid function: implications for evaluation of retinoids in cancer chemoprevention and/or chemotherapy.
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We have used a mathematical/compartmental modeling approach along with a number of rationally designed complementary in vivo and in vitro systems to investigate the effects of administration of various retinoids and/or drug combinations on normal physiological metabolism of native retinoids. The present paper focuses on our studies of the synthetic retinoid 4-HPR and our use of fairly simple mathematical/compartmental modeling techniques to investigate how this retinoid affects the metabolism of native retinoid overall, as well as in two specific tissues, the prostate and the eyes. We have presented our work with this particular retinoid and these tissues as an example of the type of studies we have been doing and to present some of the information that one can obtain using this approach. In addition, an important objective of this paper is to highlight the fact that a great deal of critical information can be derived from fairly simple mathematical/compartmental models. When used appropriately, such models provide a powerful tool to direct the design, conduct, and interpretation of experiments. The models we developed for the prostate and the eyes were used as hypotheses to direct our research efforts in both in vivo and in vitro systems. In the case of the eyes, we were able to elucidate the possible mechanisms involved in one of the most commonly reported complications (i.e., visual function abnormalities) associated with administration of an important chemopreventive and/or chemotherapeutic agent. We are in the process of further expanding our studies with the prostate as well as several other tissues in a similar manner. The immediate clinical relevance and application of our work with the eyes demonstrate the high translational potential of our approach. Without the use of the type of mathematical/compartmental modeling approach we used, which provided the basis for much of this work, we are not aware of any other way that we could have obtained the critical information that we did. We hope that the work presented here demonstrates the usefulness, power, and potential clinical applicability of a modeling approach to investigate different retinoid-based treatments as well as a variety of other chemopreventive and/or chemotherapeutic agents.