"An Overview of the Retinoids" TUMOR TIDBITS, A BIWEEKLY EMAIL NEWSLETTER FROM GULF COAST VETERINARY ONCOLOGY Number 96; April 11, 2003. ======================================================================= THIS WEEK'S TUMOR TIDBIT: An Overview of the Retinoids ======================================================================= Naturally occurring Vitamin A (Retinol) and its metabolites, as well as synthetic compounds that exert similar biologic effects, are known by the generic term “retinoids”. Natural retinoids function as necessary signaling molecules in embryonic development (heart, lungs, eyes, epithelia), and in adult animals they have profound effects on maturation and differentiation of lymphoid and epithelial cells. The synthetic retinoids have been developed over the past years to capitalize on a myriad of positive retinoid effects while minimizing toxicity associated with supraphysiologic doses of Vitamin A (i.e., hypervitaminosis A). The synthetic retinoids have been useful for a wide array of skin conditions ranging from hyperproliferative genodermatoses (ichthyosis, idiopathic seborrhea of the Cocker Spaniel) and inflammatory diseases (acne, sebaceous adenitis) to neoplasia (lymphoid and epithelial tumors) Retinoids exert their biologic effects by either activating or inhibiting gene transcription, depending upon the target cell type. They bind to nuclear receptors designated RAR (retinoic acid receptors) and RXR (retinoic acid X receptors). There are three subtypes of each receptor (a,b, and g) and these receptors typically form heterodimers (RARg/RXRa predominates in human epidermis) that bind to specific DNA sequences known as retinoic acid response elements (RARE). It is the RARE complex that mediates gene transcription. RAR and RXR are members of the steroid/thyroid/VitaminD receptor superfamily, and are highly conserved between mammalian species. The antineoplastic effect of the synthetic retinoids is probably multifactorial. One important mechanism may involve the complexing of retinoid receptors with JUN and FOS proto-oncogenes, which are constituents of the transcription factor AP1. Theoretically, formation of an inactive AP1 complex downregulates neoplastic cell proliferation while the retinoid itself promotes normal cell maturation and differentiation. A loss of normal retinoid receptor expression on cells is associated with malignant transformation, while therapy with synthetic retinoids may promote up-regulation and expression of new receptors. Another important effect in regards to cutaneous neoplasia is the enhancement of Langerhans Cell (LC) proliferation and LC production of IL-12. LC’s are the primary cellular mechanism for immunomodulation in the epidermis (where carcinomas and epitheliotrophic lymphoma often occur) and IL-12 has potent anti-tumor and anti- metastatic effects. There has been much debate about the use of retinoids and the management of cutaneous T cell lymphoma (CTCL), also known as Mycosis Fungoides. CTCL represents an epitheliotrophic neoplasm of T-lymphocytes. Epitheliotrophism restricts the neoplastic T- lymphocytes to the epidermis, hair follicle epithelium and adnexal gland epithelia until late in the disease progression, at which time generalized erythroderma, metastasis to internal organs, and circulating neoplastic cells may be identified (Sézary syndrome). Canine CTCL may present in many different forms: it may progress in an orderly fashion through the patch, plaque, nodule, and disseminated stages, or tumors may arise de novo. It may also present as exfoliative erythroderma without circulating neoplastic cells or internal metastases. The latter presentation is especially common in cats which may develop a "tissue paper" exfoliation of the epidermis. CTCL can also mimic other disease processes: alopecia similar to endocrinopathy; erythema and pruritus as would be seen with an allergic dermatitis; collarettes more typical of Staphylococcal pyoderma; or vesicles suggestive of autoimmune dermatoses (rarely). When used, topical synthetic retinoids can be locally irritating - especially to cats, and more so at higher concentrations of Retin-Aâ. The systemic synthetics have a much more manageable side-effect profile than in human beings. In cats, anorexia is the most common problem, and is often amenable to a reduction in dosage. Periocular erythema, crusting, epiphora, and blepharospasm have also been reported with Accutaneâ administration in cats. In dogs anorexia, vomiting, diarrhea, behavioral changes, and elevated liver enzymes have been reported, but all are quite rare. The most severe side effect is keratoconjunctivitis sicca, which is not uncommon. However, retinoid-induced KCS responds well to topical Cyclosporin ophthalmic suspension. Similar to human beings, dogs may exhibit elevated triglycerides and cholesterol. While not as concerning a side effect as in people, this is usually responsive to dietary fat restriction. Long-term problems associated with hypervitaminosis A in humans (osteoporosis, cheilitis, myalgias, arthralgias) are very rarely problematic for dogs and cats. Due to a risk of premature epiphyseal closure of long bones, synthetic retinoids should not be used in juvenile animals. The most concerning toxicity associated with systemic synthetic retinoids is teratogenicity, and their use in intact female dogs and cats is absolutely contraindicated. Comprehensive client education is also necessary, especially when women of childbearing age are living in the household. Etretinate use requires that women wait 2 years after dosing to attempt pregnancy. Acitretin, the active metabolite of etretinate, was developed and marketed as a replacement for etretinate, since it has a much shorter embryotoxic interval. However, some re-conversion to etretinate has since been proven, and a 2-year abstinence is now recommended for acitretin as well. If used, current recommendations include that a Shirmer tear test, a complete blood count, and a serum chemistry be assayed prior to therapy, with each rechecked after 1 month, then quarterly to biannually during maintenance therapy. A response (for most dermatologic conditions) should be noted within 6 to 8 weeks. Unfortunately, until the extreme cost associated with their use in medium and large-sized dogs can be tempered, our opportunity to study them in the clinical setting will be limited. There are hundreds of new retinoids undergoing research and development. Currently, each retinoid must be considered to have different efficacy and toxicity profiles, as the effects of each on different types of inflammatory and neoplastic diseases can vary widely. ======================================================================= As always, we hope this info helps and don't hesitate to call or email us Gulf Coast Veterinary Oncology! Kevin A. Hahn, DVM, PhD, Diplomate ACVIM (Oncology), drhahn@gcvs.com Janet K. Carreras, VMD, Diplomate ACVIM (Oncology), drcarreras@gcvs.com Glen K. King, DVM, MS, Diplomate ACVR (Radiology & Radiation Therapy), drking@gcvs.com Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: www.gcvs.com ======================================================================= Copyright © 2003, Gulf Coast Veterinary Oncology