plus 1, Paxil Blocks Tamoxifen, Lowers Survival Odds Against Breast Cancer - US News and World Report

Paxil Blocks Tamoxifen, Lowers Survival Odds Against Breast Cancer - US News and World Report

Posted: 07 Feb 2010 03:55 PM PST

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By Steven Reinberg
HealthDay Reporter

MONDAY, Feb. 8 (HealthDay News) -- Women with breast cancer who take both tamoxifen and the antidepressant Paxil may increase their risk of dying because Paxil reduces tamoxifen's effectiveness, Canadian researchers report.

"Paxil can deprive women of the benefit of tamoxifen, especially when it is used in combination with tamoxifen for a long time," said lead researcher Dr. David Juurlink, division head of clinical pharmacology and toxicology at Sunnybrook Health Sciences Center in Toronto.

"Patients who are on tamoxifen and who require an antidepressant should probably be given something different," he added.

Paroxetine (Paxil) is a selective serotonin reuptake inhibitor (SSRI) that significantly inhibits an enzyme called cytochrome P450 2D6, which is needed to metabolize tamoxifen into its active form. But this dampening effect was not seen with certain other SSRIs evaluated, including citalopram (Celexa) and venlafaxine (Effexor), the researchers said.

Patients taking Paxil and tamoxifen should talk with their doctors about changing their antidepressant, Juurlink said.

But he advised against abruptly discontinuing Paxil.

"There is a very real danger to stopping Paxil suddenly. There is a well-described withdrawal syndrome and the risk of depression becoming more severe," he said.

In addition, any transition to another antidepressant should be done gradually over several weeks, he said.

The report is published in the Feb. 8 online edition of the British Medical Journal.

For the study, Juurlink's group looked at the medical records of 2,430 women with breast cancer who began taking tamoxifen between 1993 and 2005. About 30 percent of the women were also taking an antidepressant, Paxil being the most common. Antidepressants are often prescribed to reduce hot flashes associated with tamoxifen in addition to easing symptoms of depression.

Paxil plus tamoxifen was linked to an increased risk of dying from breast cancer, and the risk increased with the amount of time the drugs were taken together, the researchers found.

Taking Paxil for 41 percent of the time that tamoxifen was also taken resulted in one extra death from breast cancer within five years of stopping tamoxifen among every 20 women taking the drugs simultaneously, Juurlink's team estimated. The more time the drugs were taken together, the greater the risk, they added.

SSRIs inhibit CYP 2D6 to varying degrees, the authors said, noting Paxil is "exceptionally potent" in that respect.

Dr. Frank Andersohn, a senior research associate at the Institute for Social Medicine, Epidemiology, and Health Economics at Charite University Medical Center in Berlin, Germany, and author of an accompanying journal editorial, said that "physicians should be aware that paroxetine and other strong 2D6-inhibiting drugs should be avoided in women treated with tamoxifen."

Fluoxetine (Prozac) is also a strong 2D6 inhibitor, the authors noted.

Another expert, Dr. Harold J. Burstein, said this paper adds to the substantial literature suggesting that drugs that affect the metabolism of tamoxifen might affect breast cancer outcomes for women taking tamoxifen.

"While the results should not alarm patients currently taking SSRIs, they do suggest that, as a practice style, patients on tamoxifen who also need SSRIs should probably seek out agents such as Effexor in preference to Prozac or Paxil," said Burstein, clinical investigator in the breast oncology center at Dana-Farber Cancer Institute, Brigham and Women's Hospital in Boston.

"The findings are also a reminder that each drug that a patient takes should be thought through carefully. If there are drugs that aren't needed, then they aren't needed and can be omitted," he added.

More information

For more information on breast cancer, visit the American Cancer Society.

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Potential New 'Twist' In Breast Cancer Detection - Redorbit.com

Posted: 05 Dec 2009 12:03 PM PST

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Posted on: Saturday, 5 December 2009, 14:10 CST

Mouse studies reveal new -- and better -- picture of stem cells that may fuel some breast cancers

Working with mice, scientists at Johns Hopkins publishing in the December issue of Neoplasia have shown that a protein made by a gene called "Twist" may be the proverbial red flag that can accurately distinguish stem cells that drive aggressive, metastatic breast cancer from other breast cancer cells.

Building on recent work suggesting that it is a relatively rare subgroup of stem cells in breast tumors that drives breast cancer, scientists have surmised that this subgroup of cells must have some very distinctive qualities and characteristics.

In experiments designed to identify those special qualities, the Hopkins team focused on the gene "Twist" (or TWIST1) – named for its winding shape – because of its known role as the producer of a so-called transcription factor, or protein that switches on or off other genes. Twist is an oncogene, one of many genes we are born with that have the potential to turn normal cells into malignant ones.

"Our experiments show that Twist is a driving force among a lot of other players in causing some forms of breast cancer," says Venu Raman, Ph.D., associate professor of radiology and oncology, Johns Hopkins University School of Medicine. "The protein it makes is one of a growing collection of markers that, when present, flag a tumor cell as a breast cancer stem cell."

Previous stem cell research identified a Twist-promoted process known as epithelial-to-mesenchymal transition, or EMT, as an important marker denoting the special subgroup of breast cancer stem cells. EMT essentially gets cells to detach from a primary tumor and metastasize. The new Hopkins research shows that the presence of Twist, along with changes in two other biomarkers – CD 24 and CD44 – even without EMT, announces the presence of this critical sub-group of stem cells.

"The conventional thinking is that the EMT is crucial for recognizing the breast cancer cell as stem cells, and the potential for metastasis, but our studies show that when Twist shows up in excess or even at all, it can work independently of EMT," says Farhad Vesuna, Ph.D., an instructor of radiology in the Johns Hopkins University School of Medicine. "EMT is not mandatory for identifying a breast cancer stem cell."

Working with human breast cancer cells transplanted into mice, all of which had the oncogene Twist, the scientists tagged cell surface markers CD24 and CD44 with fluorescent chemicals. Following isolation of the subpopulation containing high CD44 and low CD24 by flow cytometry, they counted 20 of these putative breast cancer stem cells. They then injected these cells into the breast tissue of 12 mice. All developed cancerous tumors.

"Normally, it takes approximately a million cells to grow a xenograft, or transplanted tumor," Vesuna says. "And here we're talking just 20 cells. There is something about these cells – something different compared to the whole bulk of the tumor cell – that makes them potent. That's the acid test – if you can take a very small number of purified "stem cells" and grow a cancerous tumor, this means you have a pure population."

Previously, the team showed that 65 percent of aggressive breast cancers have more Twist compared to lower-grade breast cancers, and that Twist-expressing cells are more resistant to radiation.

Twist is what scientists refer to as an oncogene, one that if expressed when and where it's not supposed to be expressed, causes oncogenesis or cancer because the molecules and pathways that once regulated it and kept it in check are gone.

This finding – that Twist is integral to the breast cancer stem cell phenotype – has fundamental implications for early detection, treatment and prevention, Raman says. Some cancer treatments may kill ordinary tumor cells while sparing the rare cancer stem cell population, sabotaging treatment efforts. More effective cancer therapies likely require drugs that kill this important stem cell population.

This study was supported by the Maryland Stem Cell Research Foundation.

In addition to Vesuna and Raman, authors of the paper include Ala Lisok and Brian Kimble, also of Johns Hopkins.

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