Old Drugs Taught New Tricks

ORLANDO—Finding new anticancer properties in drugs approved for treatment of other diseases illustrates the point that drug development doesn't end with a drug's approval. Physicians working with a new drug might discover unexpected side effects, but they can also find unexpected benefits and possibly new indications for use.Figure: C. Shun Wong, MDThree non-cancer drugs that showed potential for anticancer treatments in preclinical studies were discussed here at the American Association for Cancer Research Annual Meeting: A vitamin B12 derivative avidly picked up by cancer cells has a nitric oxide molecule attached, making it a Trojan Horse for tumors. Nembutal, the sedative and anti-seizure medication, affects the same receptors expressed in colon cancer cells as in the central nervous system and appears to inhibit colon cancer metastasis. And erythropoietin, used to treat anemia for more than a decade, can protect cognitive function in animals after whole-brain irradiation through a mechanism not related to red cell count. Treated Mice Manage Mazes Radiation therapy to the central nervous system can cause devastating late neurocognitive impairment, from mild memory loss to learning disabilities to profound dementia. But animal models given a single dose of erythropoietin (EPO) an hour after whole-brain irradiation had their learning and memory function protected as compared with irradiated animals not treated with EPO, reported C. Shun Wong, MD, Professor and Chief of the Department of Radiation Oncology at Sunnybrook Women's College Health Sciences Center in Toronto. EPO is known to cross the blood-brain barrier, Dr. Wong said, and emerging data show that EPO protects the brain against strokes, seizures, and trauma. These findings prompted the Toronto researchers to test the drug after whole-brain radiation. In preliminary experiments, 20% of mice given EPO after high radiation doses survived, compared with no survivors among the control animals. In subsequent studies, control animals receiving whole-brain irradiation later showed considerable cognitive impairment, exhibited as confusion and poor performance on memory tests “But EPO-treated, irradiated mice successfully negotiated radial maze, hole-board, and other tests as well as non-irradiated mice did,” Dr. Wong said. In a radial maze, mice are offered food at the end of radial arms in a maze; cognitively impaired animals appear to make mistakes and spend more time finding food. In the hole-board test, naturally curious mice are shown a series of holes to look through; impaired mice look into the holes more frequently, presumably because they forget they had already been there and done that. Non-irradiated animals treated with EPO did not show an improvement in cognitive function, suggesting that EPO protects the brain cells rather than improves cognitive performance, Dr. Wong said. The mechanism of action is not known; it is separate from the effect on red blood cells, he noted. EPO may have an anti-inflammatory effect that protects against neuronal and blood-vessel cell death. The moderator of a press conference highlighting the studies, Louis M. Weiner, MD, Vice President for Translational Research at Fox Chase Cancer Center, said that if EPO's neuroprotective effects are proven in humans, it could be put to this use in the clinic very soon. Vitamin Trojan Horse A vitamin B12 molecule modified with nitric oxide impairs survival signaling inside tumor cells while enhancing the apoptotic cell-death pathway. Knowing that tumor cells “crave” high volumes of vitamin B12, researchers at the Taussig Cancer Center of the Cleveland Clinic Foundation synthesized a modified vitamin B12 molecule called nitrosylcobalamin. The molecule is engineered to deliver the cellular toxin nitric oxide (NO) to cancer tumor cells. “We like to think of nitrosylcobalamin as a Trojan Horse,” said Daniel Lindner, MD, PhD, Associate Staff Member of the Center for Cancer Drug Discovery and Development. “As it circulates in the blood stream, it is inactive, and not until it is taken up into the cells does the NO cause DNA breaks and attack cellular proteins, resulting in the death of the tumor cell.” When NO is released inside the tumor cell, it triggers up-regulation of the Apo2/TRAIL cell-death pathways, he said, and also inhibits the NF-k B survival pathway. Nitrosylcobalamin in-vitro is toxic to tumor cells, relatively benign to normal cells, and significantly reduces tumors size in animal cancer models, Dr. Lindner noted. All cells, healthy and malignant, need vitamin B12 to convert homocysteine to methionine, Dr. Lindner explained. But tumor cells have a higher need for B12 and consequently produce excessive amounts of its receptors. Combining nitrosylcobalamin with interferon further elevates B12 receptor levels, and this combination regimen has produced complete tumor regression in mice. “We can give very high doses of nitrosyl to mice over a prolonged period of time and see no damage to normal tissues, while the tumors level off in size or actually disappear,” he said. The drug appears to be most effective against hematologic tumor cell lines, as well as breast, ovarian, and colon cell lines. Most exciting, Dr. Lindner said, was the therapeutic index of 10, meaning that it would take 10 times the amount of an effective dose to achieve a dose lethal to animals. “We are excited because besides pushing the cancer cell down the death pathway, the drug also blocks survival pathways,” he said, adding that the hope is that the drug will be available by the end of the year. Dr. Weiner noted that researchers at Fox Chase are testing anti-TRAIL monoclonal antibodies—“but the idea of having an additional tool in the toolbox using a very different strategy than monoclonal antibodies is very exciting,” he said.Figure: Daniel Lindner, MD, PhDNembutal & Colorectal Cancer The barbiturate Nembutal, a gamma-aminobutyric acid (GABA)-receptor agonist used in adults and children as a sedative and anesthetic and as an anticonvulsive in adults, appears to play a role outside the nervous system. Researchers reported at the AACR meeting that GABA has been found to inhibit metastases in experimental colon cancer. Premal H. Thaker, MD, a fellow in gynecologic oncology at the University of Texas M. D. Anderson Cancer Center, showed that GABA receptors have been found in mouse colon and ovarian cancer cells as well as in the brain. “The upshot [of our research] is that Nembutal was found to cause a substantial decrease in disease development in animal models injected with cells from a GABA-receptor positive colon cancer cell line,” Dr. Thaker said. Four out of 10 mice given Nembutal developed primary tumors, compared with eight of the non-Nembutal animals. Tumors that developed in the Nembutal-treated mice were a third to a quarter of the size of those in control animals, he said. And only 20% of the Nembutal-treated mice developed metastases to the liver, versus 80% of the controls. Dr. Weiner commented that as a basic-science researcher, he found this abstract particularly exciting, because “if in fact these receptors expressed on the cancer cell are important for cancer biology, it should be possible to generate a path to that receptor outside the central nervous system.” “I'm sure an effective cancer therapy would be welcome as long as it did not put people to sleep,” he joked. “But it would be welcome if you could design the drug to only target tumor cells outside the CNS, which should be possible because of the blood-brain barrier.”

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