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Scientific American Lauds PDT

Photodynamic therapy (PDT) received a major boost with a six-page feature article, "New Light on Medicine," in the January 2003 issue of Scientific American. Written by Nick Lane, an honorary research fellow at University College London, the article provides an excellent overview of the therapy as it is currently being applied in Western academic medicine.

PDT "has grown from an improbable treatment for cancer in the 1970s," says Lane, "to a sophisticated and effective weapon against a diverse array of malignancies today." The article shows how PDT is now also being used as a treatment for age-related macular degeneration and pathologic myopia (two common causes of blindness) as well as, experimentally, for coronary artery disease, AIDS, autoimmune diseases, transplantation rejection and leukemia. That is a tall order, of course, but Lane makes a convincing case that PDT offers hope for these conditions, and possibly more.

As subscribers to this newsletter already know, photodynamic therapy is based on the therapeutic interaction of light, oxygen, and a photosensitizing agent. Lane explains that the inspiration for PDT was a result of research into porphyria, a rare blood disorder characterized by extreme light sensitivity. Individuals with porphyria accumulate high levels of a natural chemical called porphyrin in their bloodstream. When activated by light, these porphyrins can be transformed into toxins that damage the skin, bones and teeth. In extreme cases, the victim's lips and gums erode to reveal red, fanglike teeth. Garlic can exacerbate an attack, and, according to Lane, an early folk remedy for the loss of hemoglobin (which contains a porphyrin) may have been to drink blood. And so we have all the elements of vampirism, as described by Bram Stoker in his classic, Dracula.

In the mid-twentieth century scientists hypothesized that the toxic effects of light-sensitive porphyrins might be useful therapeutically. As Lane reports, they made an extraordinary discovery: "If a porphyrin is injected into diseased tissue, such as a cancerous tumor, it can be activated by light to destroy that tissue." This was the origin of PDT as a cancer therapy.

Lane calls the substances at the heart of PDT "among the oldest and most important of all biological molecules, because they orchestrate the two most critical energy-generating processes in life: photosynthesis and oxygen respiration." The molecules he is referring to, chlorophyll and hemoglobin, yield, respectively, the "green" and "red" photosensitizing agents in use today.

Lane gives a clear description of these molecules. All porphyrins have in common a flat ring (composed of carbon and nitrogen) with a central hole, which provides space for a metal ion to bind to it. "When aligned correctly in the grip of the porphyrin rings, these metal atoms catalyze the most fundamental energy-generating processes in biology," says Lane. If the central atom is iron, the molecule becomes hemoglobin. If magnesium, it becomes chlorophyll. (There is even a copper-centered porphyrin, called hemocyanin, which gives the blood of horseshoe crabs a blue tint.)

The Brokers of Destruction

Metal-free porphyrins become excited when they absorb light at certain wavelengths and their electrons jump into higher-energy orbitals. Says Lane, "The molecules can then transmit their excitation to other molecules having the right kind of bonds, especially oxygen, to produce reactive singlet oxygen and other highly reactive and destructive molecules known as free radicals."

Free radicals are thought of as uniformly undesirable. However, if they are let loose inside a cancer cell, the havoc they create can be used to achieve a desirable effect: the death of the unwanted cell. "Metal-free porphyrins are not the agents, but rather the brokers, of destruction," says Lane. "They catalyze the production of toxic forms of oxygen."

Lane recounts the early history of PDT, including the pioneering work of Dr. Thomas Dougherty at Roswell Park Cancer Institute in Buffalo, New York. Dr. Dougherty is justly honored as the father of modern PDT. But as Lane points out, there were problems with his famous drug, Photofrin. First of all, Photofrin did not have a high specificity to cancer. It also gathered in other rapidly proliferating tissue, such as normal skin. As a result of the heightened photosensitivity, nearly 40 percent of Dr. Dougherty's original patients developed burns and skin rashes in the weeks after PDT.

More serious drawbacks emerged when other physicians began trying their hand at PDT. In addition to their lack of specificity, early PDT preparations suffered from a lack of potency. These preparations were impure mixtures of porphyrins that were "seldom strong enough to kill the entire tumor." Some were not very efficient at passing energy to oxygen. Others were activated "only by light that cannot penetrate more than a few millimeters into the tumor." Some natural pigments in human tissues also blocked the absorption of porphyrin. And sometimes the agent would accumulate in the superficial layers of the tumor, absorbing all of the light and preventing its penetration into the deeper layers.

Since Dr. Dougherty's seminal paper appeared in the Journal of the National Cancer Institute in 1975, many researchers from different scientific disciplines have been working to resolve these issues. Chemists have created new synthetic porphyrins, especially from chlorophyll, with greater selectivity and potency. These "second-generation" agents are capable of being activated at longer wavelengths to reach farther into tissues and tumors. Physicists have designed new light sources such as lasers and light-emitting diodes, or LEDs, that can generate particular wavelengths to activate porphyrins. Engineers have designed medical instruments (such as endoscopes) to bring light to deep-seated tumors. Pharmacologists have devised ways to reduce photosensitive side effects by minimizing the time that porphyrins spend circulating in the bloodstream. Finally, says Lane, clinicians have stepped in to design trials to "prove an effect and determine the best treatment regimens."

Searching for the Ideal Drug

"The ideal drug," says Lane, "would be not only potent and highly selective for tumors but also broken down quickly into harmless compounds and excreted from the body." He gives a brief review of nine drugs that are currently approved or in clinical trials: Levulan, Photofrin, Visudyne, Metvix, PhotoPoint SnET2, verteporphin, PhotoPoint MV9411, Antrin and Lutrin. Each of these has its own strengths, of course, but (to my knowledge, at least) none yet merits the status of the "ideal drug" so aptly characterized by Lane.

The success of PDT for the treatment of macular degeneration has inspired research activity in other fields, but, according to Lane, "also reveals the drawbacks of the treatment." In particular, he claims, even red light penetrates no more than a few centimeters into biological tissue. "This limitation threatens the utility of PDT in internal medicine -- its significance might seem to be skin deep." (I address this issue below.)

However, says Lane, "there are ways of turning PDT inward." One ingenious way is photoangioplasty, which is being used experimentally to treat coronary artery disease. Lane also discusses other potentially promising uses of PDT, including the treatment of AIDS and other autoimmune diseases and leukemias, as well as to prevent organ rejection in transplant patients.

Giving Credit Where Credit Is Due

I have several comments to make about this excellent article. First of all, though Lane rightly credits Dr. Dougherty for his groundbreaking research, he fails to mention the actual scientific founders of the field of PDT, the medical student Otto Raab and his professor, Hermann von Tappeiner, MD, of the Pharmacological Institute of Ludwig-Maximillans University in Munich. Raab and Tappeiner's work, first published in 1900, preceded that of Dougherty by three quarters of a century.These researchers are true scientific heroes who deserve to be better known.

Second, Lane doesn't clarify one of the mysteries of PDT: the actual depth of penetration of light into the human body. He repeats the often-heard statement that red light penetrates "no more than a few centimeters into biological tissues." However, Harry T. Whelan, MD, of the Medical College of Wisconsin and NASA's Marshall Space Flight Center in Huntsville, Alabama, has implied that light can penetrate tissues to depths greater than this.

In tests conducted on wrist flexor muscles in the forearm and muscles in the calf of the leg, Dr. Whelan has written, "most of the light photons at wavelengths between 630-800 nm travel 23 cm through the surface tissue and muscle between input and exit at the photon detector." This range of wavelengths (630-800 nm) is precisely the range at which most commercial and experimental photosensitizers now in use operate. Twenty-three centimeters, the depth to which "most of the light photons" penetrate, is more than nine inches.

By focusing on the exciting developments in PDT, the Scientific American article is acknowledging a growing trend in oncology away from conventional cytotoxic treatments and towards innovative approaches that are highly selective for cancer. Although PDT is already FDA-approved for some kinds of cancer, macular degeneration and skin disease, it is still underappreciated and underutilized. Scientific American has been published continuously since 1845 and is among the most influential journals in the world. This article will serve as a wake-up call to scientific opinion-makers worldwide that PDT has finally "arrived," while laying the foundation for even more exciting discoveries and announcements in the months and years to come.

--Ralph W. Moss, Ph.D.

References:

Lane N. New light on medicine. Scientific American, January 2003.
http://www.sciam.com/article.cfm?colID=1&articleID=000B4130-5C6C-1DF7-9733809EC588EEDF

Dougherty TJ et al. Photoradiation therapy. II. Cure of animal tumors with hematoporphyrin and light. J Natl Cancer Inst 1975;55:115-21.

Whelan HT et al. The NASA light-emitting diode medical program
-- Progress in space flight and terrestrial applications.
http://www.bioscanlight.com/word_3studies_i4_NN_343_21_eye1_56/the_nasa_light.htm

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The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.