When Flutamide Stops Working: MAP Kinase Stimulation of Prostate Cancer
Growth
New
Discoveries About Hormonal Therapy Failure in Treatment of Prostate
Cancer
by
J. STRAX
PSA Rising, New York, November 5, 2002 -- Scientists have discovered
that the antiandrogen drug Flutamide, widely used to treat prostate
cancer, actually switches on a non-hormonal molecule known to cause
cancerous cells to grow and proliferate. This work, which earned an
award from the American Urological Association, is described in the
November 1 issue of the journal Cancer Research.
The authors says that their discovery "raises a concern for using
[Flutamide] in the complete-androgen-ablation therapy in prostate cancer
treatment and provides a possible pathway that might contribute to the
[Flutamide] withdrawal syndrome."
"It's a real surprise, that the same compound that kills cancer
cells also makes them grow," says Chawnshang Chang, Ph.D., corresponding
author and director of the George Whipple Laboratory for Cancer Research
at the University of Rochester Medical Center. "The effect of the
drug reverses completely."
When prostate cancers first occur, they are dependent on androgens
for growth and can be treated successfully with androgen ablation therapy.
However, after prolonged antiandrogen therapy, eventually the cancer
acquires the ability to proliferate. Finding out exactly how this happens
is a key step to prevention and better treatment.
In 1998 Chang found molecular evidence of how antiandrogen drugs, which
up to a point can halt the disease, under certain conditions can spur
prostate-cancer cells to grow. Working with George Wilding of University
of Wisconsin Comprehensive Cancer Center he reported that antiandrogens,
hydroxyflutamide, (Flutamide) bicalutamide (Casodex), cyproterone acetate
and other compounds such as genistein and RU486, "can promote the
interaction between the androgen receptor (AR) and its coactivator."
He went on to show that HER2/Neu
oncogene could increase growth rate and raise PSA "at a very
low androgen concentration, a condition very similar to the prostate
cancer patients undergoing androgen ablation therapy." At that
time the researchers looked to see if Flutamide, widely used in androgen
ablation therapy, could block this action of Her2/Neu, and found it
could not.
In the most recent work on this problem of how anti-androgens fail,
Yi-Fen Lee, Ph.D., now an assistant professor in the Department of Urology
at Rochester, studied cancer cells from four men, comparing the cells
from early in their disease to cells after hormonal therapy became ineffective.
Chang and Lee's award-winning research found that, in addition to blocking
uptake of testosterone by targeting a protein known as the androgen
receptor, Flutamide switches on a molecule known as mitogen-activated
protein (MAP) kinase. It is a signaling molecule which promotes cell
growth and is known to play a role in diseases like breast and prostate
cancer. Chang and Lee found it in much higher levels in the prostate
cancer cells that had survived hormone therapy. Incidentally,
tThis effect is not confined to chemical drugs. . Biopsies of men who
had undergone orchiectomy (surgical castration) found that the reatment
switched on the cancer-promoting molecule, (MAP)
kinase.
"In all of the more than 30,000 men who die of prostate cancer each
year, the cancer cells have become capable of growing even when we starve
the cells of testosterone," says Edward Messing, M.D., professor and
chair of urology who treats hundreds of men for prostate cancer each
year. "In each one of those men, there's been a fundamental change,
so that the molecule we've targeted for stopping the cancer is no longer
involved in the disease. It's at this point that the disease becomes
a killer. Finding an additional potential target for preventing this
switch is surprising and significant."
Despite the drawbacks, the scientists stress that current treatment,
including hormonal therapy, is still the best option available for patients
whose cancer has spread beyond the prostate gland. "These drugs are
necessary for patients who otherwise have few options," says Lee. "However,
these findings do raise some concerns that should be investigated further.
Perhaps these findings will help lead to a new drug target so that men
with this disease can be treated more effectively."
The project was done by Chang, Lee, Lin, Messing and Jiaoti
Huang, Ph.D., assistant professor of pathology and laboratory medicine
at The Cancer Center, University of Rochester Medical Center, Rochester,
NY; Franky Chan of the Chinese University of Hong Kong; and medical
oncologist George Wilding of the University of Wisconsin. The research
was funded by the National Institutes of Health.
Read the Abstract: Cancer
Res 2002 Nov 1;62(21):6039-44 Activation
of Mitogen-activated Protein Kinase Pathway by the Antiandrogen Hydroxyflutamide
in Androgen Receptor-negative Prostate Cancer Cells. Lee
YF, Lin WJ, Huang J, Messing EM, Chan FL, Wilding G, Chang C. George
Whipple Laboratory for Cancer Research, Departments of Pathology, Urology,
Radiation Oncology, and The Cancer Center, University of Rochester Medical
Center, Rochester, New York 14642
Related Articles
FREE FULL TEXT: Cancer Res 1999 Jan
15;59(2):279-84 Activation
of mitogen-activated protein kinase associated with prostate cancer
progression. Gioeli D, Mandell JW, Petroni GR, Frierson
HF Jr, Weber MJ. Department of Microbiology and Cancer Center, University
of Virginia Health Sciences Center, Charlottesville 22908, USA.
Life Sci 2002 Sep 27;71(19):2257-66 Regulation
of the expression of protein kinase C isoenzymes in rat ventral prostate:
effects of age, castration and flutamide treatment.
Montalvo L, Sanchez-Chapado M, Prieto JC, Carmena MJ. Department
of Biochemistry and Molecular Biology, University of Alcala, E-28871
Alcala de Henares, Spain.
FREE FULL TEXT: PNAS May 11, 1999 Vol. 96,
Issue 10, 5458-5463 From
HER2/Neu signal cascade to androgen receptor and its coactivators: A
novel pathway by induction of androgen target genes through MAP kinase
in prostate cancer cells Shuyuan Yeh, Hui-Kuan Lin, Hong-Yo
Kang, Tin Htwe Thin, Ming-Fong Lin, and Chawnshang Chang. George Whipple
Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation
Oncology, and The Cancer Center, University of Rochester, Rochester,
NY 14642; and Department of Biochemistry and Molecular Biology, University
of Nebraska Medical Center, Omaha, NE 68198
Add/View
Comments to this page. To avoid receiving spam, use our address
[email protected]
E-mail
[email protected] 