science/technology
LET THERE BE LIGHT AND LET IT HEAL First developed for cancer treatment, pbotodynamic therapy is branching out to many other clinical applications A. Maureen Rouhi C&EN Washington
To date, Photofrin is approved for treatment of esophageal cancer in the U.S., Canada, Japan, France, and the Nethereople bathed in light could be a lands. It is available for lung cancer in Jacommon sight in medical clinics in pan, France, the Netherlands, and Germathe future. They won't be there to ny, and for bladder cancer in Canada. In get a good tan, but rather to heal through Japan, Photofrin also can be used to treat photodynamic therapy. This up-and- gastric and cervical cancers. Furthermore, it coming form of treatment is becoming in- is in clinical trials in several countries for creasingly accepted for certain forms of treatment of head and neck cancer, as well cancer. Now, with more and better com- as Barrett's esophagus. This latter disease is pounds to work with, researchers are apply- a precancerous condition that could lead to ing the treatment to various other diseases. esophageal cancer. It is caused by acid rePhotodynamic therapy is based on the flux, which may be triggered by stress. action of light on certain chemicals In a typical treatment of cancerous tucalled photosensitizers. These light-sensitive molecules accumulate in tumors through mechanisms that are not well understood. When illuminated, the photosensitizers unleash reactive species that can kill cancer cells. According to the generally accepted mechanism of action, when most photosensitizers are illuminated by light of the correct wavelength and power, they absorb energy that they, in turn, transfer to oxygen, which ordinarily exists in the triplet electronic state. The energy transferred by the photosensitizer converts triplet oxygen to singlet oxygen, an extremely reactive species that is destructive to cells. In photodynamic therapy, the tissues Blue light activates the photosensitizer that are meant to be destroyed are selec- formed in precancerous skin lesions after tively iUuminated and the damage is con- application of a precursor. fined only to those areas. Other sites are not affected, both because the photosensi- mors with Photofrin, the patient receives tizers have no toxicity in the absence of an intravenous injection of the photosensilight and because they tend to accumulate tizer as an outpatient and then waits for 24 in the target tissues. to 48 hours. This waiting period allows So far, only one photosensitizer— the drug to accumulate in the tumor and called Photofrin (porfimer sodium)—has to be removed from normal tissues. The gained regulatory approval for photody- patient returns to the clinic after the waitnamic therapy of any kind. Photofrin is a ing period and the tumor is illuminated for porphyrin-type compound developed at 10 to 30 minutes, often using fiber optics. Roswell Park Cancer Institute, Buffalo, The patient goes home the same day. N.Y. In 1988, QLT PhotoTherapeutics, "There is one side effect," notes David Vancouver, British Columbia, bought the Dolphin, a chemistry professor at the Unirights to Photofrin and has since been reg- versity of British Columbia, Vancouver, istering it around the world. and vice president of technology develop-
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22 NOVEMBER 2, 1998 C&EN
ment at QLT. He says Photofrin stays in the skin for approximately 30 days after treatment, making the patient sensitive to strong light. On a good day in Florida, "you'll need to wear a hat and gloves," he says. But compared with the nausea, pain, and loss of hair that often accompany chemotherapy and radiation therapy, this side effect seems benign. The effective localized treatment and the ease with which it is applied coupled with the relatively minor side effect make photodynamic therapy very appealing. "I really believe that in the next millennium photodynamic therapy is going to be one of the very important modalities in medicine," says Dolphin. With these attractive features of photodynamic therapy and Photofrin's successful commercialization, the race is on to develop so-called second-generation photosensitizers. Many researchers continue to explore porphyrin-type compounds, manipulating them to achieve improvements over Photofrin. One area where improvement is being sought is light penetration. Light penetrates deeper into tissues as its wavelength increases. In its current applications, Photofrin is activated at 630 nm. With tumors, for example, Photofrin's effect penetrates through only a few millimeters. A photosensitizer that can be excited at longer wavelengths will penetrate more deeply, reaching farther into the tumor. QLT's second-generation compound— benzoporphyrin derivative monoacid ring A, or Verteporfin—has several advantages over Photofrin. It is activated at 690 nm and thus it can be used to treat more deeply seated or larger tumors than is possible with Photofrin. It builds up rapidly in target tissues and clears swiftly from normal tissues, allowing light treatment to begin within five minutes after the drug is introduced, compared with the two
