Antioxidants

The outermost layer of the skin, the stratum corneum, is metabolically active and requires antioxidants and specific nutrients to maintain its integrity and proper function. Topically applied antioxidants reduce free radicals in skin cells and substantially inhibit the biochemical cascades responsible for infected and inflamed skin. There is an expressed concern in the scientific community that oral antioxidants may reduce oxidizing free radicals created by radiotherapy. However, there is significant evidence that exogenous antioxidants produce beneficial effects in numerous cancer cell lines. Multiple animal and human studies have demonstrated an increased effectiveness of cancer therapeutic agents, as well as decreased adverse effects, when given concomitantly with topical antioxidant application.



One of the most effective antioxidants in the terms of free radical scavenging is 3,4-dihydroxyphenyl ethanol or hydroxytyrosol (HT). HT is a simple phenol found predominantly in the aqueous fraction of olive pulp. HT application has been found to prevent both radiation-induced protein damage and radiation-induced oxidative DNA damage. The protective effects provided by HT are relevant to the radiation-induced DNA damage manifested by single- and double-strand breaks in epidermal and dermal skin cells. Furthermore, several studies have shown that HT inhibits leukocyte and macrophage activation, as well as their subsequent infiltration into epidermal and dermal skin cells. HT’s modulation of immune function helps reduce the inflammatory processes associated with radiation dermatitis.



n-3 and n-6 Polyunsaturated Fatty Acids (PUFAs)

The stratum corneum is composed of epidermal cell remnants surrounded by a combination of biological lipids. The epidermal cells producing these remnants require certain amino acids to sustain stratum corneum formation, while the lipid barrier requires specific PUFAs to maintain stratum corneum integrity. A mixture of sphingolipids, cholesterol, and free fatty acids forms the intercellular membrane bilayers of the stratum corneum which regulate barrier function. PUFAs have also been shown to reduce or prevent numerous side effects associated with radiotherapy, including radiation dermatitis.

In particular, linolenic (n-3) and linoleic (n-6) PUFAs were found to protect against radiation dermatitis while potentiating radiation treatment via lipid peroxidation. The fatty acids’ effect on tumor growth depends on the balance between n-3 and n-6 PUFAs and antioxidants. The proper formulation of potent antioxidants, n-3 and n-6 PUFAs significantly enhances radiotherapy while preventing fatty acid-induced oxidative stress on epidermal and dermal skin cells. PUFAs play important roles as regulators of the complex inflammatory processes established shortly after radiation-induced skin injury. PUFAs exert their functions in the form of protective phospholipids anchored in epidermal cell membranes or as soluble lipoic mediators of the inflammatory response. Linolenic n-3 fatty acids specifically inhibit proinflammatory interleukin-1, interleukin-6 and tumor necrosis factor-alpha (TNF?) production. Modulating the balance of lipid inflammatory mediators is an extremely valuable treatment for inflammatory skin disorders such as radiation dermatitis. Both n-3 and n-6 PUFAs balance lipid mediators and improve the reconstitution of epithelial integrity following skin injury.



There exist numerous n-3 and n-6 PUFA sources, several of which significantly protect against radiation-induced tissue damage. Canola oil has been reported as being one of the most potent antimutagenic compounds available for topical administration. Canola oil induces intracellular oxidative stress and apoptosis in human cancer cells while inhibiting inflammatory leukocyte activity and subsequent skin irritation. Similarly, safflower oil protects against normal cell damage. Olive oil is another PUFA that has been shown to exhibit substantial anticancer and antioxidative effects. In addition, olive oil specifically prevents radiation-induced skin injury by protecting normal DNA and sustaining skin cell homeostasis. Altogether, the proper balance of certain PUFAs provides important protection against radiation dermatitis.

Vitamins and Vitamin Derivatives

In addition to antioxidant application, specific micronutrients, including vitamins and vitamin derivatives, have been deemed invaluable for nourishing skin and protecting against radiation dermatitis. Moreover, micronutrient deficiency actually mimics radiation damage by causing DNA single- and double-strand breaks and oxidative lesions in normal skin cells. Supplementing micronutrients via the topical application of vitamin precursors and vitamin derivatives protects against radiation-induced skin injury. Accordingly, retinyl palmitate, the precursor to retinoic acid and a biological form of vitamin A, has been shown to prevent radiation-induced DNA damage and erythema in normal skin cells. The topical application of retinyl palmitate counteracts vitamin A depletion caused by radiotherapy and promotes recovery. Retinyl palmitate also helps treat radiation-induced skin ulcerations by nourishing the migratory epithelial cells responsible for closing the wound41. Overall, retinyl palmitate has been found to increase radiation’s effect on tumor cells in vivo, while decreasing symptoms associated with radiation dermatitis.

Ascorbyl palmitate is another important vitamin derivative that nourishes human skin and helps prevent radiation dermatitis. The micornutrient is a lipid-soluble derivative of ascorbic acid capable of penetrating the stratum corneum to target sites of cell-signaling pathways that are not accessible to water-soluble molecules. Ascorbyl palmitate has been found to maintain tissue integrity while protecting against erythema and desquamation via its potent moisturizing effect. Furthermore, ascorbyl palmitate is an effective free radical scavenger and guards well against radiation-induced DNA damage in epithelial cell lines. Ascorbyl palmitate may play a critical role in preventing radiation-induced tissue damage by providing proper cell nourishment and antioxidative protection.

Cholecalciferol (CF), or vitamin D3, is hydroxylated in the kidney to produce 1,25-dihydroxyvitmain D, which is an active metabolite and hormone that sustains proper cell function by binding to vitamin D receptors. In particular, the derivative demonstrates strong immunoreactivity in skin and hair follicle vitamin D receptors, thereby protecting against radiation toxicity and preventing radiation dermatitis. The topical application of certain micronutrients and subsequent uptake by the stratum corneum, epidermis and dermis, has a synergistic effect with radiotherapy. Altogether, CF, ascorbyl palmitate and retinyl palmitate have been shown to increase tumor response during radiation treatment while protecting against radiation dermatitis.

Amino Acids

Symptoms associated with radiation dermatitis are a result of tissue breakdown involving a decline in both collagen and glycosaminoglycans, as well as from changes in their chemical structure and 3-dimensional organization. The transdermal delivery of certain amino acids has been shown to restore collagen synthesis and deposition, while thickening the epidermal skin layer. Selected amino acids have been shown to inhibit the genotoxicity of reactive oxygen species in dermal and epidermal skin cells during radiotherapy. In particular, N-acetyl-l- cysteine (NAC) exhibits significant protective effects on skin, including the extracellular inhibition of mutagenic agents from exogenous sources such as irradiation.

NAC modulates reactive metabolic pathways, protects normal DNA and nuclear enzymes, and prevents the formation of carcinogen-DNA adducts. The amino acid exerts its effects via its potent antioxidative properties, as well as its unique ability to sequester nitric oxide (NO) and reverse TNF? toxicity in human cells. NO production was found to be significantly increased in cancer patients, especially in individuals being treated for breast cancer. Breast cancer patients are known to exhibit increased levels of both nitrate and nitrite, which may be in response to the inflammation characteristic of breast tumor growth. Since radiotherapy further increases NO activity and induces inflammation, the topical application of amino acids such as NAC should be considered. NAC reacts directly with NO to reduce the increased NO generation while reversing harmful glutathione depletion.



Aritcle by Dr. Darlene McCord