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By Allen Cone
A 150-year-old drug used to increase blood flow throughout the body appears to improve cancer treatment radiation by making tumors more sensitive to the therapy, according to a study.
Researchers at Ohio State University found papaverine, which is sold under the brand names Para-Time SR, Papacon and Pavacot in pill form, inhibits the oxygen-consuming and energy-making components of cells, called mitochondria, and sensitizes model tumors to radiation. The findings were published Tuesday in the journal Proceedings of the National Academy of Sciences.
"We know that hypoxia limits the effectiveness of radiation therapy, and that's a serious clinical problem because more than half of all people with cancer receive radiation therapy at some point in their care," Dr. Nicholas Denko, a professor of radiation oncology at OSU's Comprehensive Cancer Center, said in a press release. "We found that one dose of papaverine prior to radiation therapy reduces mitochondrial respiration, alleviates hypoxia, and greatly enhances the responses of model tumors to radiation."
Radiation kills cancer cells directly by damaging DNA and indirectly by generating damage-causing molecules called oxygen radicals. But hypoxic conditions, in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level, reduce radiation-induced DNA damage and the effective toxicity of a dose of radiation.
"If malignant cells in hypoxic areas of a tumor survive radiation therapy, they can become a source of tumor recurrence," Denko said. "It's critical that we find ways to overcome this form of treatment resistance."
Cancer cells require high levels of oxygen for rapid growth. When blood vessels are poorly formed, the tumor is not efficient at delivering oxygen and other nutrients. This leads to dead, necrotic cells surrounded by areas of hypoxia.
In addition, cancer cells in hypoxic regions are resistant to radiation and beyond the the reach of chemotherapy.
Researchers have attempted to overcome radiation resistance by delivering more oxygen to the tumor, Denko said.
"But these attempts have met with little clinical success because tumors have poorly formed vasculature," he said. "We took the opposite approach. Rather than attempting to increase oxygen supply, we reduced the oxygen demand, and these findings suggest that papaverine or a derivative is a promising metabolic radiosensitizer."
Papaverine is found in the opium poppy, but the structure and pharmacological composition is different from morphine-related opiates.
In 1848, George Merck, the son of Emanuel Merck, founder of the Merck corporation, discovered the drug as a student of German chemists Justus von Liebig and August Hofmann.
Aside from being used against muscle spasms, the drug has been prescribed to treat certain abnormal heartbeats, including to increase blood flow to the heart. An injectible form of the drug has also been used for erectile dysfunction.
The study "represents a potential landmark in the six-decade-old quest to eliminate hypoxia as a cause for radiotherapy treatment failure," Dr. Mark W. Dewhirst, a professor in the Department of Radiation Oncology at Duke University School of Medicine, wrote in an accompanying commentary.
