Topical application of chemotherapy drug may improve appearance of aging skin

Topical application of the chemotherapy medication fluorouracil appears to reduce potentially precancerous skin patches and improve the appearance of sun-damaged skin, according to a report in the June issue of Archives of Dermatology, one of the JAMA/Archives journals.

Fluorouracil stops the body from synthesizing thymine, a building block of DNA, according to background information in the article. This drug is used to treat cancers of the colon, head and neck, pancreas and other organs. In early studies of patients with cancer undergoing treatment with systemic fluorouracil, clinicians noticed changes in skin appearance, which led to the development of a topical therapy for the treatment of actinic keratoses (skin lesions that may develop into skin cancer).

Dana L. Sachs, M.D., of the University of Michigan Medical School, Ann Arbor, and colleagues evaluated molecular and clinical changes in the skin of 21 healthy volunteers with actinic keratoses and sun-damaged skin. Participants applied 5 percent fluorouracil cream to the face twice daily for two weeks; skin biopsies and clinical evaluations were performed at the beginning of the study and periodically throughout treatment. Photographs were also taken at the beginning of the study and after one, two, four, six, 10 and 24 weeks, and were evaluated by three dermatologists who were not involved in examining the patients during the study. Nineteen patients completed all aspects of the study, and 20 responded to a questionnaire at week 10.

The number of actinic keratoses was significantly reduced following treatment, from an average of 11.6 lesions to an average of 1.5. Clinical evaluations also identified overall improvements in aging-related damage, including decreases in fine (small) and course (large) wrinkling, lentigines (dark skin spots), hyperpigmentation (skin that has become darker) and sallowness (a yellow skin tone).

One day after the final fluorouracil treatment, testing of the skin biopsies revealed an increase in the levels of compounds related to skin injury, inflammation and degradation of the extracellular matrix (the non-living tissue that supports skin), in addition to the precursor of collagen, which rebuilds damaged skin. “Topical fluorouracil causes epidermal [outer skin layer] injury, which stimulates wound healing and dermal remodeling resulting in improved appearance,” the authors write. “The mechanism of topical fluorouracil in photo-aged skin follows a predictable wound healing pattern of events reminiscent of that seen with laser treatment of photo-aging.”

The treatment was generally well tolerated. On the 10-week questionnaire, most patients rated their skin as improved (19, or 95 percent) and were willing to undergo the therapy again (17, or 89 percent).

“For patients in whom a course of topical fluorouracil is indicated for the treatment of actinic keratoses, there will likely be the additional benefit of a restorative effect from sun damage; this may provide further motivation for these patients to undergo the rigorous treatment,” the authors conclude. “It is possible that for some patients topical fluorouracil may have an important role against photo-aging. For others, however, it may not be cosmetically acceptable given that a standard course of therapy may last two to three weeks and the ensuing reaction can persist for several more weeks. Undoubtedly, there will be patients who desire a therapy such as topical fluorouracil for cosmetic purposes given the relatively low cost of this therapy compared with ablative laser resurfacing.”

(Arch Dermatol. 2009;145[6]:659-666. Available pre-embargo to the media at www.jamamedia.org.)

Isotretinoin and suicide: Epidemiological study shows no association

London, Ontario, Canada — Suicidal behavior among patients taking isotretinoin represents an uncommon, idiosyncratic phenomenon, according to the author of a recent study of nationally representative patient data spanning a decade.

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For the duration of the experiment, I consumed approximately 25mg doxycycline in the morning on top of my usual stack of supplements. Unfortunately, due to laziness and lack of time, I don’t have any objective observational data of the effects (i.e., comparative photos taken under identical conditions), so I’ll instead talk about how things appeared. I wouldn’t normally be satisfied with such subjective measurement, but the outcome was so resoundingly bad that I don’t think it matters! :/

Initially, I was perplexed that an ulcer I developed in my mouth was seeming to take far longer than normal to heal; however, this may have something to do with my expectation that healing, especially of oral wounds, would be accelerated.

The one important factor that I intended to measure was if doxycycline supplementation would do anything to increase the production of collagen in the skin. As someone who has experienced the obvious and profound (and positive) effect of oral retinoids on skin texture and quality, I was somewhat disappointed in doxycycline’s effect. Not only was there no (subjective) reduction in the number, severity, or depth of the photo-aging induced wrinkles on my face, but the doxycycline appeared to be making the condition worse!

About two weeks into the experimental period, I was continually dismayed every time I looked into the mirror at what appeared to be a ‘thinning’ of the skin on my face, particularly noticeable on my forehead, as well as more noticeable wrinkles and an overall reduction in any remnants of the youthful glow that Father Time has yet to wrestle from me. Even within the short duration of the experiment, the skin on my face started to take on that ‘papery’ stiffness one associates with the skin of the elderly.

It really was difficult to persist with the regimen in the face of what I felt to be outright failure of my idea, but I did anyway.

About ten days after ceasing the medication, I already feel my skin has mostly regained its normal texture, but I can’t be sure because I didn’t carry out any real quantitative analysis. It has definitely reverted to its normal elasticity.

All in all, I recommend not employing doxycycline to improve the quality of one’s skin. As for why this happened, I can only speculate. If we assume that doxycycline does in fact inhibit the breakdown of collagen, I suppose it could have caused a ’stiffening’ of the skin, which then caused it to appear more wrinkly and deeply lined. The perceived reduction in facial subcutaneous fat my have just been my interpretation of the changed texture. Perhaps it skews the ratio of collagen to elastin, again resulting in a reduced elasticity of the skin.

Regardless, I seem to have discovered for myself why there is apparently no research taking place regarding doxycycline as a potential ‘cosmaceutical’!

This is because, while the ability to degrade the matrix is extremely important in growth and wound healing, if the processes of synthesis and degradation fall out of balance in favour of degradation, the overall amount of collagen will decrease.

In youth, these processes are in balance, but as we age, the degradative enzyme activity begins to overpower that of synthesis, leading to a loss of skin quality. Other factors that increase MMPs are photodamage and smoking.

In the past, I’ve boosted my skin’s balance in favour of collagen synthesis with isotretinoin, which worked beautifully but has drawbacks that in my opinion make it unacceptable for chronic use (cracking lips, sun sensitivity, etc.). I’ve also heard that the skin’s response to collagen-synthesis stimulating retinoids decreases with age.

So, in theory, one could boost its overall levels by instead interfering with the breakdown of collagen by inhibiting MMPs.

At present, the only MMP inhibitor that’s available readily and cheaply is doxycycline hyclate, an antibiotic often used to combat acne. Apparently, by taking a subantimicrobial dose (i.e., too little to kill bacteria) one can benefit from its anti-MMP activity while minimizing its side effects. Doxycycline is also used in this way in dentistry, where it is used to facilitate healing of the connective tissue in the gums.

There was also a study where doxycycline’s effect on wound healing was investigated because it was suspected it may *interfere* with normal wound healing as a side-effect, but it was instead found that the wounds actually healed either at the same rate or faster.

So, lately I’ve been noticing the accumulation with age and decades of intense sunlight a slight loss of skin elasticity (yes, wrinkles), so I decided to start taking 25mg/day doxycycline for a couple of months and see if this has any effect on the quality of my skin. I’ve taken some ‘before’ photos that highlight the problem, and I intend to compare these with pictures taken in 1 and 2 months to see if I can identify any change.

The literature is at first glance almost entirely free of this kind of experiment, with most papers focussing on doxycycline’s antibacterial and anti-inflammatory effects for the treatment of acne and rosacea. I’m sure there’s a good reason for this that I in my limited capacity don’t have time to dig up, so I’m pressing ahead regardless.

I’ll post the results, including before/after shots and analysis in about a month

Here’s some reading in the meantime:

• Inhibition of matrix metalloproteinases: a new skin care frontier
• Matrix metalloproteinases
• Doxycycline

Which is to say, you’re less likely to get melanoma if you spend all day out in the sun smoking cigarettes. Of course, your chances of getting lung cancer will be greatly enhanced, but whatever.

It appeared to be the degree of ’skin aging’ – the loss of elastin and collagen that makes skin look old and saggy (a process that occurs sooner in smokers) – that conferred resistance to melanoma.

I don’t really know what to make of this! Personally, I’d avoid the cigarettes but continue with my fairly lax approach to UV protection. What do you think?

Here’s the abstract:

Skin aging from ultraviolet irradiance and smoking reduces risk of melanoma: epidemiological evidence.

Anticancer Res. 2008 Nov-Dec;28(6B):4003-8. PMID: 1919266

Grant WB.
Sunlight, Nutrition, and Health Research Center (SUNARC), P.O. Box 641603, San Francisco, CA 94164-1603, USA. wbgrant@infionline.net

Long-term smoking appears to be inversely correlated with development of melanoma. Chronic ultraviolet (UV) irradiance also reduces and/or delays the development of melanoma. Thus, a common process is indicated. To examine the link between smoking and melanoma, articles reporting the relation between incidence of lung cancer and melanoma for individuals were sought. A very strong inverse correlation (r = -0.96) was found between the standardized incidence ratios for lung cancer and melanoma, passing through the value of 1 for each with a slope of -0.74. Smoking increases skin aging or elastosis in a manner similar to that of UV irradiance. Development of elastosis seems to explain why long-term smoking and chronic UV irradiance reduce the risk of melanoma. Further work is required to elucidate the mechanism whereby elastosis retards and reduces the development of melanoma.

The article is reasonably technical, but I’ll summarize the results here:

Green tea polyphenol (GTP) supplementation in mice prevents photocarcinogenesis (i.e., skin cancer). I’ve not mentioned this before, so here’s a link to a review on the matter.

Salient points from above-mentioned review:

Extensive in vitro and in vivo studies have been conducted to determine the anti-UV carcinogenic effects of green tea. It has been found that the oral administration of GTPs (a mixture of polyphenolic components isolated from green tea) in the drinking water of mice results in significant protection against UV-induced skin carcinogenesis in terms of tumor incidence, tumor multiplicity and tumor size, compared to those mice that were not given GTPs in their drinking water.

The mice that were given crude water extracts of green tea as a sole source of drinking water developed a lesser number of tumors compared to those mice that were not given water extracts of green tea. The administration of GTPs in drinking water or the topical application of EGCG also induced partial regression or inhibition of the tumor growth of established skin papillomas in mice.

The researchers in this case showed that GTP supplementation in mice reduced the levels of inflammation markers cyclooxygenase-2, prostaglandin E2, proliferating cell nuclear antigen, and cyclin D1, and proinflammatory cytokines tumor necrosis factor-alpha, IL-6, and IL-1-beta. UVB-induced DNA damage was rapidly resolved in the GTP-supplemented mice compared with the wild type mice.

The major contribution of this study was that all these effects appear to be mediated through interleukin 12.

Personally, I have been supplementing with Now Foods EGCg Green Tea extract, available from bulknutrition.com. At 4 capsules per day, this is apparently equivalent to 12 cups of green tea. Hopefully this will keep me skin cancer free!

First of all, in case you’re wondering how I know he’s mad, or at least some kind of evil genius, just look at his picture!

Lead researcher Prof. Daniel Cohen-Or of the Blavatnik School of Computer Sciences at Tel Aviv University

“Beauty can be quantified by mathematical measurements and ratios. It can be defined as average distances between features, which a majority of people agree are the most beautiful,” says Prof. Cohen-Or. “I don’t claim to know much about beauty. For us, every picture in this research project is just a collection of numbers.”

The Professor’s algorithm is based on an analysis of 93 different different faces that were ranked for attractiveness by a group of German people. I think that might have been a flaw in his methodology, but it seems to have worked so I’ll run with it.

All the different characteristics of the faces, like the ratios of the measurements of the eyes, nose, mouth, etc. were distilled down into an algorithm that then changes the picture of your face to conform to these ideals.

Interestingly, the machine doesn’t quite work when the face of a familiar celebrity is given as input. Turned out most people were a little perturbed by the results when faces like those of Woody Allen or Brigitte Bardot were altered by the machine, but the faces of everyday people came out fine. This is probably because the beauty of celebrities is an illusion fostered by media-driven mass hypnotism.

Ordinary people turned into slightly prettier ordinary people. Note: Originals on the top, modifieds on the bottom.

Adapted from materials provided by Eurekalert