Mar 30 2004
Drugs approved for treatment of specific maladies sometimes show unexpected benefits. Researchers at the 95th annual meeting of the American Association for Cancer Research demonstrated highlighted how some drugs may one day offer previously unforeseen benefits for patients.
The research was presented here today at the 95th Annual Meeting of the American Association for Cancer Research. Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist Nembutal: Abstract No. 5513
A drug that acts as a "downer" on the central nervous system also works to suppress metastasis in an experimental model of colon cancer, according to researchers from M.D. Anderson Cancer Center in Houston, Tex.
The barbiturate Nembutal, or pentobarbital, is known to have similar effects in the brain as gamma-aminobutyric acid (GABA), a neurotransmitter-inhibiting amino acid. Nembutal acts in the manner of a GABA receptor agonist. GABA acts through cell surface receptors, and GABA receptor membrane proteins are present not only in the brain, but on colon and ovarian cancer cells as well.
Premal Thaker, M.D., and colleagues, tested whether Nembutal activated GABA receptors on the cancer cells both in culture and in vivo using a mouse model for colon cancer. After confirming the presence of GABA receptors in the colon cancer cell lines, the researchers documented a marked reduction in cellular cAMP concentrations in colon cancer cell lines treated with Nembutal.
In animal models, nude mice were injected in the cecum or spleen with KM12SM, a GABA receptor positive colon cancer cell line. Nearly half as many mice treated with Nembutal (4 of 10) developed primary tumors after injection in the spleen as the non-Nembutal treated mice (8 of 10). When the cells were injected into the cecum, 7 of ten mice treated with Nembutal developed tumors, compared to 9 of ten non-treated mice. Tumors that developed in the Nembutal treated mice were substantially smaller than the tumors that grew in non-Nembutal treated mice. The tumors in the cecum and spleens of barbiturate treated mice were only a third to a quarter the size of tumors from the controls.
Nembutal reduced metastasis to the liver in the mice injected with tumor cells in the spleen. Only 20 percent of barbiturate-treated mice exhibited metastatic spread to the liver, while 80 percent of non-barbiturate-treated mice developed liver metastasis.
The findings, Thaker said, suggest that Nembutal is a potent inhibitor of colon cancer metastasis. It is possible that the GABA receptor pathway, commonly found on colon and ovarian cancer cells may be useful in the clinic, but further research work will be necessary.
Erthropoietin improves learning and memory impairment after whole brain irradiation: Abstract No. 3125
A drug that is normally used to fight anemia in cancer patients may also help brain tumor patients retain thinking, memory and concentration after radiation treatment, said Shun Wong, M.D., a researcher with Sunnybrook and Women's College Health Science Centre, Toronto.
Wong said that in animal studies, a single dose of erythropoietin (EPO) one hour after whole brain irradiation dramatically improved learning and memory function in mice.
"In our study, the animals that received radiation treatment alone showed considerable cognitive impairment," Wong said. "They acted confused and performed poorly on tests of memory. "
"On the other hand, mice that were first treated with radiation and then systemically injected with EPO maintained cognitive function that was no different than control mice, and substantially better than the irradiated mice that did not receive EPO," Wong said.
Mice treated with EPO after whole brain radiation successfully negotiated radial maze and hole-board tests as well as non-irradiated mice, Wong said. While EPO-treated irradiated mice demonstrated no behavioral or learning impairment, animals treated with EPO alone showed no boost or improvement in cognitive function.
Radiation treatment of brain tumors often leaves patients with late neurocognitive impairment. Patients complain of difficulty in concentration, memory and thinking. The application of EPO treatment in conjunction with radiation therapy to reduce brain tumor mass holds promise for human brain cancer patients to protect innate cognitive function during and after radiation treatment.
"We conclude that systemic treatment of EPO protects animals from learning and memory impairment after whole brain radiation," Wong said. Further studies are underway to determine the cellular and molecular changes in the brain due to EPO neuro protective treatment.
Effects of nitrosylcobalamin on NF-kB survival signaling and antitumor activity of Apo2L/TRAIL: Abstract No. 5580
Acting on the knowledge that many tumor cells crave the micronutrient cobalamin - more commonly known as vitamin B12 - a team of cancer researchers from Cleveland has designed a modified B12 molecule that delivers a cellular toxin to kill tumor cells.
The "Trojan Horse" modification of the vitamin B12 molecule induces tumor cell mechanisms to cause cell death.
Daniel Lindner, M.D., Ph.D. and Joseph Bauer, Ph.D. described how tumor cells have a desperate need for high amounts of vitamin B12, suggesting a new and devious method to deliver targeted drugs to the cancer.
"Tumors crave Vitamin B12 because cancer cells have an imperative need for methionine in protein production," Lindner said. "All cells need vitamin B12 to convert homocysteine to methionine, but cancer cells have a greater need."
To satisfy their cellular craving for the vitamin, tumor cells produce excessive amounts of the receptor that attaches to available blood-borne vitamin B12. The receptors import the vitamin inside of the cell membrane. Since tumor cells produce far more - ten times or more - the number of receptors for Vitamin B12 than normal cells, the concentrations of the vitamin build up within tumor cells.
Taking advantage of tumor cell uptake of large quantities of vitamin B12, Bauer modified the vitamin to include nitric oxide. The new molecule, called nitrosylcobalamin, latches onto B12 receptors and delivers a knockout punch to the tumor cell.
"Tumor cells hungrily ingest the modified Vitamin B12, just as they do the natural micronutrient," Bauer said.
Inside the tumor cell, however, the nitric oxide component of the targeted drug is released, triggering cellular events leading to up-regulation of genes causing apoptosis--or programmed cell death.
Lindner and Bauer documented how the elevated levels of nitric oxide in the tumor cells inhibit a molecular pathway that normally promotes cell survival. By hampering the activity of the NFkB pathway, elevated nitric oxide promotes apoptosis in tumor cells. Nitrosylcobalamin also up-regulates the Apo2/TRAIL pathway directly leading to apoptosis.
The novel technology is potent against tumor cells in culture, while relatively benign to normal cells. In animal models, the "Trojan Horse" dramatically reduces tumor size. In combination with interferon treatment, which encourages further elevation of Vitamin B12 receptor levels in tumor cells, nitrosylcobalamin leads to complete tumor regression in mice.
"In principle, this targeted therapeutic will be effective in human tumors," Lindner said. "Testing will tell."
Lindner and his colleagues are members of the Taussig Cancer Center and the Department of Cancer Biology at the Cleveland Clinic.
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