• Information
  1. Retinoid Physiology
  2. Developmental Role of Retinoids
  3. All Trans Retinoic Acid
  4. Side Effects of all trans-Retinoic Acid
  5. Isotretinoin
  6. Other Retinoids

A. Retinoid Physiology [1,2]

1. Retinoic Acid (all-trans)
   1. Binds retinoic acid receptors (RARa, b, c), coded on chromosome 17q21
   2. RARa involved in chromosomal translocations in APML
2. Cis-9-retinoic acid (C9RA)
   1. Binds retinoid X receptors (RXRa, b, c) and RAR (RARa, b, c)
   2. Involved in regulation of fat metabolism and other pathways
3. Isotretinoin
   1. Cis-13-retinoic acid
   2. Binds only RARa, b, c
4. Cytosolic retinoic acid (RA) binding protein 1 (CRABP1)
   1. CRABP1 binds to all RA
   2. Complex of CRABP1-RA interacts with cytochrome P450 system (CYP 3A)
5. Conversion of RA to C9RA
   1. RA is converted to active cis-9-retinoic acid (C9RA) form by CYP 3A
   2. C9RA binds to Retinoid X Receptor (RXR) and activates it
6. RXR and PPARg
   1. RXR-RA binds to, and stimulates, PPAR gamma (PPARg) and other proteins
   2. PPARg is responsible for stimulation of peripheral adipocytes and uptake of lipids

B. Developmental Role of Retinoids

1. Clear role in limb formation
2. Also required for normal brain development

C. All Trans Retinoic Acid [3,4]

1. Acute promyelocytic leukemia (APML) overexpresses abnormal retinoid receptor
2. In APML, RARa on chrom 17 is translocated to chrom 15 and overexpressed
3. Retinoids can induce differentiation of APML cells
4. Clinically, ~85% induction rate with all-trans retinoic acid in APML [5,6]
   1. Relapses occur in 1-23 months (mean, 4 months)
   2. All-trans retinoic acid maintenance improves disease free and overall survival [5]
5. Synthetic retinoid Am80 induced complete remission in two relapsed APML patients [6]

D. Side Effects of all trans-Retinoic Acid

1. Typical of most retinoids
   1. Dry Skin
   2. Headache and Pseudotumor cerebri
   3. Triglyceride and cholesterol elevations
2. Some effects common only in APML patients
   1. Retinoic acid syndrome
   2. Cardiovascular - CHF with fluid overload; pulmonary edema
   3. Pulmonary - respiratory distress, pleural effusion
3. Retinoic Acid Syndome (~25% of patients)
   1. Leukocytosis (>20K) following induction with retinoic acid
   2. Capillary leak syndrome with pulmonary infiltrates and pleural effusions
   3. Weight Gain
   4. Myeloid cell infiltration of multiple organs
   5. Syndrome prevented with full doses of cytotoxic chemotherapy
   6. Syndrome may be mediated by differentiated myeloid cells

E. Isotretinoin (Accutane®) [7]

1. Synthetic vitamin A derivative (cis-13-retinoic acid)
   1. Used for severe acne
   2. Also improves survival in high risk neuroblastoma [8]
2. Dramatic clearing with prolonged periods of remission in severe acne
3. Physiologic Activities
   1. Reduction of sebum production
   2. Anti-inflammatory effects
   3. Corrects altered keratinization (restores normal epithelization)
   4. Reduces proliferation and induces differentiation in neuroblastoma cells
4. Side Effects
   1. Major Teratogen - full contraception is absolutely required; no effects on sperm
   2. Ocular: decreased night vision
   3. Skin: dry skin, pruritus, photosensitivity, peeling, hair loss
   4. Mucous membranes: eye irritation, dryness (all membranes), epistaxis
   5. Liver function abnormalities (AST, ALT; ~15% of patients)
   6. Lipid Anomalies: hypertriglyceridemia, hypercholesterolemia, reduced HDL [9]
   7. Patients with initial >89 mg/dL increase in triglycerides are at highest risk for developing hyperlipidemia and insulin resistance syndromes [9]
   8. Vertebral hyperostoses
   9. CNS: headaches, benign intracranial hypertension
   10. Serum ßHCG must be done to rule out pregnancy before prescribing
   11. Informed consent required and adequate contraception must be used
   12. In women, isotretinoin is then started during menses
   13. Psychiatric: depression, psychosis, suicide
   14. Most side effects similar to that observed for vitamin A overdose

F. Other Retinoids [1,11]

1. Tretinoin (Retin-A®, Renova®)
   1. Generally well tolerated topical vitamin A derivative with excellent activity
   2. May cause erythema, dryness, scaling, irritation in skin
   3. Gel supplied as 0.01% and 0.025% strengths
   4. Creams as 0.025%, 0.05%, and 0.1%
   5. Also as a 0.05% liquid for more diffuse application
   6. May help prevent photodamage and "aging" effects on skin
2. Adapalene (Differin®) [11]
   1. Synthetic retinoid analog (derivative of naphthoic acid)
   2. Decreases formation of comedones and inflammatory skin lesions
   3. Appears to be as effective as, and better tolerated than, tretinoin
   4. Apply 0.1% gel once daily in evening after washing affected areas
   5. Can cause erythema, dryness, scaling, burning
3. Tazarotene (Tazorac®) [12]
   1. Acetylinic retinoid, 0.1% gel and cream now approved for acne
   2. As effective as tretinoin or adapalene for treatment of acne vulgaris
   3. Gel is more irritating than tretinoin or adapalene
   4. Cream may be better tolerated but degree of efficacy is not well documented
4. Bexarotene (Targretin®) [10]
   1. Binds retinoic acid X receptor (RXRa, b, c) only and stimulates transcription
   2. Does not bind RAR
   3. In cutaneous T cell lymphoma, may induce apoptosis [4]
   4. Oral formulation approved for use in refractory cutaneous T cell lymphoma

References

1. Shulman AI and Mangelsdorf DJ. 2005. NEJM. 353(6):604
2. Carr A, Samaras K, Chisholm DJ, Cooper DA. 1998. Lancet. 351(9119):1881
3. Frankel SR, Eardley A, Heller G, et al. 1994. Ann Intern Med. 120(4):278
4. Warrell RP Jr. 1996. Annu Rev Med. 47:555
5. Tallman MS, Andersen JW, Schiffer C, et al. 1997. NEJM. 337(15):1021
6. Takeshita A, Shibata Y, Shinjo K, et al. 1996. Ann Intern Med. 124(10):893
7. Brown SK and Shalita AR. 1998. Lancet. 351(9119):1871
8. Matthay KK, Villablanca JG, Seeger RC, et al. 1999. NEJM. 341(16):1165
9. Rodondi N, Darioli R, Ramelet AA, et al. 2002. Ann Intern Med. 136(8):582
10. Bexarotene. 2000. Med Let. 42(1075):31
11. Treatment of Acne. 1997. Med Let. 39(995):19
12. Tazarotene. 2002. Med Let. 44(1132):52
13. Accutane Review. Med Let. 44(1139):82