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PubMed:Search for peer-reviewed info about cancer

Widely used anti-nausea drug, dexamethasone, may interfere with breast cancer chemotherapy

by J. Strax

March 4, 2004 - Dexamethasone (trade name Decadron), a drug widely used to prevent nausea and other side effects in patients receiving chemotherapy, has been tested at the University of Chicago to see how it affects breast cancer cells.

In the March 1 issue of the journal Cancer Research, the investigators report that the drug unfortunately prevents the therapy from working efficiently on breast tumor cells.

Dexamethasone, a synthetic steroid, is routinely given to women with breast cancer just before they receive chemotherapy with paclitaxel (Taxol) or doxorubicin, two drugs commonly used to treat breast cancer. Dexamethasone is also given to men with prostate cancer and women with ovarian cancer before treatments with Taxol, docetaxol (Taxotere) and/or carboplatin.

Dr. Conzen's laboratory study shows that pretreatment with dexamethasone reduces the ability of paclitaxel and doxorubicin to kill breast cancer cells.

"Nearly every patient receiving chemotherapy for breast cancer also receives dexamethasone pre-treatments that may make therapy less effective," said Suzanne Conzen, M.D, assistant professor of medicine at the University of Chicago and director of the study. "With breast cancer one wants the best tumor reduction possible, but we have evidence that the benefits provided by routine treatment with dexamethasone may cause decreased chemotherapy-induced tumor cell death."

Conzen's team became suspicious nearly four years ago when they discovered that a group of steroid hormones know as glucocorticoids could inhibit death in certain cell types, including breast epithelial cells. This made them begin to question the wisdom of treating breast cancer patients with dexamethasone (known as Dex), an artificial glucocorticoid.

DEX use before chemo needs "re-evaluation"

A careful search of the literature on dexamethasone uncovered another surprise. "Remarkably," the authors note, no clinical studies had ever addressed the potential effects on tumor response of administering Dex before routine chemotherapy for breast cancer.

To study these effects at the molecular level, Conzen's team devised a laboratory system that mimicked the usual clinical administration of dexamethasone in this setting. They found that pretreatment of breast cancer cells with dexamethasone reduced the cell death rate following exposure to either paclitaxel or doxorubicin by more than 25 percent, even though the two drugs rely on very different mechanisms to cause tumor cell destruction.

Since dexamethasone actually kills certain types of cells such as lymphocytes and is effective treatment for lymphoma, the researchers wondered why Dex destroys one type of cancer cell yet protects another from cell death.

Using a technique that measures the effects of a drug on gene expression, they found that dexamethasone consistently upregulated 45 genes in breast cancer cells and that these genes differed from those found to be regulated by dexamethasone in earlier studies using lymphocytes.

They then focused their attention on two genes that were upregulated in breast cells by dexamethasone -- SGK-1 and MKP-1. SGK-1 has been previously shown to prevent cell death in brain and breast cells. MKP-1 can protect prostate cancer cells and its increased expression is associated with breast, ovarian and pancreatic cancers.

They found that both SGK-1 and MKP-1 played a major role in dexamethasone's effects, protecting breast cancer cells from the effects of both paclitaxel and doxorubicin. Blocking these proteins, on the other hand, reversed the drug's unwanted effects on cancer cell survival.

PSA Rising asked Dr. Conzen if she thinks any such problem with Dex may occur in its use before chemotherapy for prostate cancer.

"We have not looked at prostate cancer cells in our in vitro model so I can't say," Conzen replied. "It might hold with prostate or might not, depending on A) how the dexamethasone affects the prostate epithelium (they do contain GR) and B) how DEX might affect the prostate cancer stroma (cellular environment)."

"I get the impression that stromal (surrounding cell) -prostate epithelial cell interactions play more of a role in determining tumor outcome in experimental models of prostate cancer than in breast cancer," she said.

A recent study of hormone refractory prostate cancer patients at Columbia Presbyterian Medical Center found that dexamethasone monotherapy before starting chemotherapy did not enhance response rate to Taxotere and Emcyt (docetaxel and estramustine).

Dr. Conzen emphasized that in this particular prostate cancer trial "the Dex was not given right before each chemo dose so the interaction with chemo may be different." In chemotherapy for breast cancer, she added, "we think Dex may prevent the cells from having an optimal apoptotic response because of the genes it turns on before chemo - in breast cancer Dex is always given right before chemo."

Conzen and her co-authors are not yet ready to stop using dexamethasone, a very effective drug for prevention of side effects from chemotherapy. But Conzen suggests that the evidence is mounting that oncologists "should begin to study the effects of using this drug routinely as part of breast cancer therapy."

"The widespread use of drugs such as dexamethasone before chemotherapy," the authors conclude, "requires reevaluation because of the observed inhibition of chemotherapy efficacy."

Additional authors of the study were Wei Wu, Shamita Chaudhuri, Deanna Brickley, Diana Pang and Theodore Karrison of the University of Chicago. The National Institutes of Health, the Department of Defense, the Schweppe, Concern, Entertainment Industry and the University of Chicago Cancer Research Foundations supported the research.

This page reported by J. Strax, last updated March 9 2004

Research background

Microarray Analysis Reveals Glucocorticoid-Regulated Survival Genes That Are Associated With Inhibition of Apoptosis in Breast Epithelial Cells. Suzanne D. Conzen et al. Cancer Research 64, 1757-1764, March 1, 2004

Glucocorticoid Receptor-mediated Protection from Apoptosis Is Associated with Induction of the Serine/ Threonine Survival Kinase Gene, sgk-1 Suzanne D. Conzen
et al, University of Chicago, Chicago, Illinois J. Biol. Chem., Vol. 276, Issue 20, 16649-16654, May 18, 2001

Contrasting study

Possible mechanism of dexamethasone therapy for prostate cancer: suppression of circulating level of interleukin-6. Akakura K, Suzuki H, Ueda T, Komiya A, Ichikawa T, Igarashi T, Ito H. Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan. Prostate. 2003 Jul 1;56(2):106-9.

alt.support.cancer.breast - Frequently asked Questions - drugs

Surviving Through Chemotherapy - Bladder Cancer Webcafe- Cytoprotectant drugs

The Glucocorticoid Receptor Mediates a Survival Signal in Human Mammary Epithelial Cells Timothy J. Moran ... and Suzanne D. Conzen, University of Chicago. Cancer Research 60, 867-872, February 15, 2000

Effects of glucocorticoid on proliferation, differentiation, and glucocorticoid receptor expression in human ovarian carcinoma cell line 3AO. Xu MJ, Fang GE, Liu YJ, Song LN. "Dex inhibited the proliferation of 3AO cells accompanied by morphological changes in concentration- and time- dependent manner." Department of Gynecology and Obstetrics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Acta Pharmacol Sin. 2002 Sep;23(9):819-23.

Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer. Weitzman AL... Petrylak DP. Columbia Presbyterian Medical Center, New York. J Urol. 2000 Mar;163(3):834-7.

A Glucocorticoid-Responsive Mutant Androgen Receptor Exhibits Unique Ligand Specificity: Therapeutic Implications for Androgen-Independent Prostate Cancer Aruna V. Krishnan , Xiao-Yan Zhao , Srilatha Swami , Lars Brive, Donna M. Peehl , Kathryn R. Ely and David Feldman Endocrinology Vol. 143, No. 5 1889-1900

Clinical Trials overseen by National Institutes of Health (NIH)

NCCN Clinical Trials Locator by Hospital

The Treatment Challenge of Hormone-Refractory Prostate Cancer Julia Kish et al 2001. Moffit Cancer Center .pdf

Prostate Nomogram: an online tool to help physicians and patients predict the outcomes of treatment options. At MSKCC website.