Light-activated therapy and radiation combined effectively for treating tumors

Dartmouth researchers report in the March 1 issue of Cancer Research they have discovered an effective combination therapy to treat tumors. In the journal, which is a publication of the American Association for Cancer Research, the researchers report that administering light-activated, or photodynamic, therapy (PDT) immediately before radiation therapy appears to kill tumors more effectively than just the sum of the two treatments.

“Our study shows that the close combination of the two treatments complement each other, allowing more effective therapy for the same delivered dose,” says Brian Pogue, the lead author, an Associate Professor at Dartmouth’s Thayer School of Engineering and a Research Scientist at Harvard Medical School.

PDT is used to treat a variety of illnesses, from lung cancer to age-related blindness. The treatment uses a light-activated drug to kill tumor tissue. The drug, verteporfin in this study, is designed to accumulate within tissues with tumor-like characteristics, such as leaky vasculature and rapidly growing cells.

Pogue and his colleagues studied the effectiveness of a combined approach for administering the photodynamic therapy and subsequent radiation for treating a mouse tumor. The multidisciplinary research team is composed of faculty from Dartmouth’s Thayer School of Engineering, Dartmouth Medical School, the Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, and Massachusetts General Hospital.

“This finding could spark a new direction and new applications for PDT,” says Pogue. “The key feature of this treatment is that the mechanism of cellular damage appears to be significantly targeted towards the cellular mitochondria, unlike radiation treatment that inflicts DNA damage.”

Verteporfin is a specially designed porphyrin molecule. Porphyrins occur widely in nature, are light sensitive and play an important role in various biological processes. Heme is one notable porphyrin found in hemoglobin, and it is responsible for oxygen transport and storage in tissues. Chlorophyll is another type of porphyrin. When activated by a beam of light, porphyrins interact with oxygen in the tissues, producing a kind of oxygen, called singlet state oxygen, which is toxic to cells. This photochemical process is an efficient way to kill tissues by producing massive doses of singlet state oxygen.

Oxygen in tumors is a key component in both radiation therapy and PDT. The presence of oxygen significantly increases the ability of the therapy to induce singlet oxygen, which in turn more effectively kills the tumor tissue. “In this study, we found that verteporfin appears to increase oxygen within the tumor,” says Pogue, “and this makes the subsequent radiation more effective.”

Previous studies by Pogue and colleagues have shown that PDT with verteporfin targets the mitochondria (responsible for cellular respiration), but only if the verteporfin is delivered in a manner that allows distribution throughout the tumor with partial clearance from the blood vessels. This means that the drug is cleared rapidly from the blood stream by the kidneys and the liver, which is a key feature in being compatible with outpatient medical treatment. This approach of targeting the tumor tissue rather than the blood vessels was further developed in the study.

The researchers discovered that applying PDT to kill the mitochondria of the tumor cells caused a decrease in oxygen consumption, yet oxygen was still being delivered to the tumor tissue. This phenomenon resulted in an increase in available oxygen within the tumor, which improves PDT’s ability to induce singlet-state oxygen and also allows the immediately-following second therapy of radiation to be more effective. Increased oxygenation of tumors is well-known to significantly increase the radiation sensitivity of the tissue, according to Pogue.

The study was carried out in subcutaneous radiation-induced fibrosarcoma (RIF-1) tumors in mice. The tumor-killing effects were quantified by following the shrinkage of tumor volume over time after the treatments. The most effective therapy was determined by measuring the delay in the regrowth rate of the tumor, which is a standard method in cancer therapy research.

Pogue’s co-authors on this study were: Julia O’Hara, Research Associate Professor of Radiology at Dartmouth Medical School; Eugene Demidenko, Research Associate Professor at the Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center and Adjunct Associate Professor of Mathematics at Dartmouth College; Carmen Wilmot, Radiology Laboratory Technician at Dartmouth Medical School; Isak Goodwin, a Dartmouth alum from the class of ’01 who will attend Drexel University Medical School this fall; Bin Chen; Research Associate at Dartmouth’s Thayer School of Engineering, Harold Swartz, Professor of Radiology at Dartmouth Medical School, and Tayyaba Hasan, Professor at Wellman Laboratories of Photomedicine at the Massachusetts General Hospital and Harvard Medical School.

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This study was funded by: the National Cancer Institute through grants RO1 CA78734, PO1 CA84203 and by the Electron Paramagnetic Resonance Center for the Study of Viable Systems at Dartmouth Medical School supported by the National Center for Research Resources.