Key Points

Photodynamic therapy (PDT) results in a five-fold increase in levels of Ki67
Baseline immunostaining for the tumor suppressor gene p53 may be a predictor of response to treatment
Utility of PDT for the treatment of dermatoheliosis and the changes of skin aging

National report — Photodynamic therapy (PDT) results in a fivefold increase in levels of Ki67, a protein important to the growth and development of new skin cells.

Information such as this, which quantifies our understanding of how PDT works, is crucial to optimizing treatment and advancing the field, says Jeffrey S. Orringer, M.D., director of the Cosmetic Dermatology & Laser Center, University of Michigan, Ann Arbor, Mich.

“Our study represents an attempt to quantify, on a molecular level, epidermal and dermal matrix changes following PDT,” Dr. Orringer says.

Dr. Hirsch believes the information can help clinicians better use the skin sensitizers and lasers that are currently available, and guide future developments in the field.

 

Trial parameters

The trial enrolled 25 patients who were generally healthy, had clinical evidence of significant photodamage, and had no history of significant cosmetic interventions at the site examined.

The study involved the use of the photosensitizer 5-aminolevulinic acid (5-ALA, Levulan) and a single-pass treatment with a pulsed dye laser.

While the majority of PDT procedures occur on the face, the forearm was used in the study, because baseline and multiple follow-up skin punch biopsies held a potential for scarring.

 

Study findings

In addition to the increase in Ki67, researchers found a 1.4-fold increase in epidermal thickness; a 70-fold increase from baseline in cytokeratin 16 levels; and significant upregulation of procollagen I messenger RNA (2.65-fold increase) and procollagen III messenger RNA (3.32-fold).

There also was a correlation between baseline p53 levels and subsequent production of cytokeratin 16 in response to therapy.

“Using the topical photosensitizer clearly gave us more consistent and quantitatively greater changes in the skin compared to historical studies using nonablative laser therapy alone.

“This tracks very nicely with the bulk of the clinical evidence in this field, including clinical split-face studies,” Dr. Orringer tells Dermatology Times.

 

Baseline immunostaining

Another interesting finding was that baseline immunostaining for the tumor suppressor gene p53 — an excellent indicator of the extent of photodamage — may be a predictor of response to treatment.

Baseline staining for p53 correlated with levels of cytokeratin 16 at acute time points after treatment, and this, in turn, was linked to collagen production.

“Patients with greater sun damage at baseline were more susceptible to a controlled injury from the treatment and, therefore, were able to produce more collagen in response to it.

“This implies that we may be able to get greater changes from this kind of a treatment among patients who have significant sun damage,” Dr. Orringer says.

 

Dose response curve

“In general, our working hypothesis is that the stronger the treatment applied to the skin, the more dermal remodeling one is likely to get out of it.

“While the concepts of less downtime and exceptionally safe treatments are terrific, we have to find that happy medium between keeping things convenient for patients and providing an intervention that is effective,” Dr. Orringer says.

 

Collagen production

Dr. Orringer believes that enhanced collagen production is a key response for durable improvement in photodamaged skin. He has found that the variability of response often depends on the degree of insult the procedure delivers to the skin.

“When we use ablative carbon dioxide laser resurfacing, the wound-healing responses are very highly organized, very consistent from patient to patient.

“At the opposite end of the spectrum, with very mild interventions like microdermabrasion or non-ablative laser treatments, some patients did very well and produced lots of collagen, and others had very little change at all,” he says.

 

Contact time

In the current study, Dr. Orringer says that the photosensitizer was left on for three hours “to ensure there was adequate absorption to allow for true photodynamic therapy effects, to be sure that we weren’t looking at changes that were the result of the laser therapy alone.”

He says the clinical trend toward significantly shorter contact time for photosensitizer application prior to use of the laser, for the convenience of the patients and flow of the office, “may not be optimal and is not necessarily based on molecular and cellular biology.

“It probably takes somewhat longer for the Levulan to be taken up by cells than most practitioners allow the material to remain on the skin prior to treatment. I’m not sure that clinicians are always taking full advantages of the PDT effect.”

 

Ongoing research

Ongoing research includes looking at evolving fractionated laser technologies and minimally ablative technologies, “to see what type of dermal changes, if any, we can create by simply disturbing the epidermis,” Dr. Orringer says.

“We think that we are developing a working molecular model that may one day be used to predict the clinical value of new technologies as they arise,” Dr. Orringer says.

 

Confirmation

“It certainly is exciting to get molecular data that confirms anecdotal and clinical study evidence of the utility of PDT for the treatment of dermatoheliosis and the changes of skin aging,” says Ranella J. Hirsch, M.D., president of the American Society of Cosmetic Dermatology and Aesthetic Surgery.

“A significant next step for this line of research would be experimentation with alternative incubations to see what the molecular findings are with each,” she says.

For more information: Orringer JS, Hammerberg C, Hamilton T, Johnson TM, Kang S, Sachs DL, Fisher G, Voorhees JJ. Molecular effects of photodynamic therapy for photoaging. Arch Dermatol. 2008 Oct;144(10):1296-302. PMID: 18936392