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Blocking Cancer-Causing Gene Improves Radiation Effectiveness, Jefferson Researchers Find
November 09, 2006Inhibiting a particular cancer-causing gene can enhance the cell-killing effects of radiation, a team of radiation oncologists and cancer biologists at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia have found.
Adam Dicker, M.D., Ph.D., professor of radiation oncology at Jefferson Medical College and his co-workers used an increasingly common animal model, the zebrafish, and antisense technology to show that the drug flavopiridol works by blocking the activity of the gene, cyclin D1, which is made in excessive amounts in about half of all breast cancers. Using similar techniques in the future, the scientists say, may enable researchers to better gauge the effects of drugs.
According to Dr. Dicker, flavopiridol was found to inhibit cyclins, a family of genes vital to cell functioning. When it was initially tested in clinical trials, it was found to be toxic in humans. But in the laboratory, it added to the cell-killing effects of ionizing radiation, which is used to treat cancer. No one was sure why.
To find out, Dr. Dicker and his group turned to zebrafish. If they understood how the drug was causing toxicity, they or someone else could potentially design molecular copycat drugs that worked just as well, but were less toxic.
"Zebrafish enabled us to add a vertebrate system to examine both efficacy and toxicity issues," he notes.
In the work, Dr. Dicker and his co-workers first showed that flavopiridol-treated zebrafish embryos were much more sensitive than normal zebrafish to the effects of radiation. Then, believing that this effect stemmed from the drug's ability to block cyclin D, they used antisense technology to "knock down" - reduce the expression of - several cyclin genes, including cyclin D1.
Antisense DNA drugs work by binding to RNA messages from a target gene. The genetic code in the RNA cannot be read, essentially turning off the gene.
"We think that the radiosensitization is primarily due to cyclin D1," Dr. Dicker says. "We were able to genetically reduce the amount of cyclin D1 through the antisense technology, and when compared to embryos treated with radiation and flavopiridol, we saw that the effects were essentially identical. This shows the power of the system. Flavopiridol hits five or six cyclins and this allows us to find which cyclins are responsible for the radiosensitive effects.
"Theoretically, if we had a drug that inhibited several cyclins, we could understand the effect of inhibiting each cyclin by knocking it down with antisense," he says. "The technique helps explain drug function."
Thomas Jefferson University Hospital
To find out, Dr. Dicker and his group turned to zebrafish. If they understood how the drug was causing toxicity, they or someone else could potentially design molecular copycat drugs that worked just as well, but were less toxic.
"Zebrafish enabled us to add a vertebrate system to examine both efficacy and toxicity issues," he notes.
In the work, Dr. Dicker and his co-workers first showed that flavopiridol-treated zebrafish embryos were much more sensitive than normal zebrafish to the effects of radiation. Then, believing that this effect stemmed from the drug's ability to block cyclin D, they used antisense technology to "knock down" - reduce the expression of - several cyclin genes, including cyclin D1.
Antisense DNA drugs work by binding to RNA messages from a target gene. The genetic code in the RNA cannot be read, essentially turning off the gene.
"We think that the radiosensitization is primarily due to cyclin D1," Dr. Dicker says. "We were able to genetically reduce the amount of cyclin D1 through the antisense technology, and when compared to embryos treated with radiation and flavopiridol, we saw that the effects were essentially identical. This shows the power of the system. Flavopiridol hits five or six cyclins and this allows us to find which cyclins are responsible for the radiosensitive effects.
"Theoretically, if we had a drug that inhibited several cyclins, we could understand the effect of inhibiting each cyclin by knocking it down with antisense," he says. "The technique helps explain drug function."
Thomas Jefferson University Hospital
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Supervolcano eruption -- in Sumatra -- deforested India 73,000 years ago
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Possible Link Studied Between Childhood Abuse and Early Cellular Aging
Children who suffer physical or emotional abuse may be faced with accelerated cellular aging as adults, according to new research from Butler Hospital and Brown University.
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Radiation therapy is effective in achieving local control and palliation in patients with pancreatic neuroendocrine tumors (PNTs), despite such tumors being commonly considered resistant to radiation therapy.
Nuclear weapons: Predicting the unthinkable
If a nuclear weapon were detonated in a metropolitan area, how large would the affected area be? Where should first responders first go? According to physicist Fernando Grinstein, we have some initial understanding to address these questions, but fundamental issues remain unresolved.
New cancer target for non-Hodgkin's lymphoma
Physician-scientists from Weill Cornell Medical College have discovered a molecular mechanism that may prove to be a powerful target for the treatment of non-Hodgkin's lymphoma, a type of cancer that affects lymphocytes, or white blood cells.
Johns Hopkins researchers track down protein responsible for chronic rhinosinusitis with polyps
A protein known to stimulate blood vessel growth has now been found to be responsible for the cell overgrowth in the development of polyps that characterize one of the most severe forms of sinusitis, a study by Johns Hopkins researchers suggests.
Experts: Failure to focus on farming will undermine global climate agreement and increase hunger
Alarmed by a substantial oversight in the global climate talks leading up to the United Nations Climate Change Conference in Copenhagen next month, more than 60 of the world's most prominent agricultural scientists and leaders underscored how the almost total absence of agriculture in the agreement could lead to widespread famine and food shortages in the years ahead.
Extinct moa rewrites New Zealand's history
DNA recovered from fossilised bones of the moa, a giant extinct bird, has revealed a new geological history of New Zealand, reports a study published this week in the Proceedings of the National Academy of Sciences.
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