'Erectile Dysfunction' Drugs Heighten Natural Anti-cancer Activity
December 07, 2006
Sildenafil and other "impotence drugs"
that boost the production of a gassy chemical
messenger to dilate blood vessels and produce
an erection now also show promise in unmasking
cancer cells so that the immune system can recognize
and attack them, say scientists at the Johns
Hopkins Kimmel Cancer Center.
Tests at Hopkins on mice with implanted colon
and breast tumors showed that tumor size decreased
two- and threefold in sildenafil-treated animals,
compared to mice that did not get the drug.
In mice engineered to lack an immune system,
tumors were unaffected, proof of principle,
the scientists say, that the drug is abetting
the immune system's own cellular response to
cancer.
In a report published in the Nov. 27 issue
of the Journal of Experimental Medicine, the
Hopkins team says boosted levels of the chemical
messenger nitric oxide appear to dampen the
effects of a specialized cell that diverts the
immune system away from tumors, allowing swarms
of cancer-attacking T-cells to migrate to tumor
sites in the rodents.
Lab-grown cancer cells treated with sildenafil
showed similar results, as did tissue samples
taken from 14 head and neck cancer and multiple
myeloma patients.
Sildenafil, marketed under the trade name
Viagra, is one of a class of drugs used to treat
erectile dysfunction in millions of men, and
in recent years, its ability to stimulate the
production of NO has been investigated by experts
in diseases linked to the activity of blood
vessels and blood components.
The new Hopkins study homes in on a tactic
used by cancers to avoid detection by the immune
system by turning elements of that system to
its own advantage, says Ivan Borrello, M.D.,
assistant professor at the Johns Hopkins Kimmel
Cancer Center.
Borrello and his colleagues found that tumors
exploit nitric oxide-producing immune cells
to create a sort of "fog" that keeps
them hidden from white blood cells (T-cells)
that mount attacks on tumors.
These NO-producing cells, a.k.a. myeloid-derived
suppressor cells (MDSCs), normally use nitric
oxide to help bring the immune system back down
to surveillance levels after an "attack
mode" response to foreign material.
The impotence drugs seem to reverse this process,
stopping the production of nitric oxide by MDSCs
thereby allowing other immune cells to "see"
the cancer and attack it, says Paolo Serafini,
Ph.D., a research fellow in Borrello's laboratory
and lead author on the paper. Nitric oxide is
infamous among city dwellers as a component
of air-polluting smog, but is gaining importance
in medical research for its cell-signaling duties
and its ability to divert soldiering T-cells
that patrol and protect.
The Hopkins team also analyzed gene expression
patterns of the myeloid-derived suppressor cells
and found that sildenafil blocked two genes
regulating enzymes -- arginase and nitric oxide
synthase -- which are key to triggering immune
suppression via MDSCs. Borrello's team found
that the arginase enzyme, which metabolizes
a dietary supplement called L-arginine, also
contributes to dampening the immune system through
MDSCs much like nitric oxide, and its production
can be reversed by sildenafil.
"Impotence
drugs won't cure cancer," Borello cautioned,
"but could be used in addition to standard
chemotherapy or immunotherapy treatments."
The investigators are planning human studies
to begin in the next year.
Funding for the study was provided by the
Italian Association for Cancer Research.
Coauthors include Kristin Meckel, Michael
Kelso, Kimberly Noonan, Joseph Califano, and
Wayne Koch from Johns Hopkins; and Luigi Dolcetti
and Vincenzo Bronte from the Istituto Oncologico
Veneto in Padua, Italy.
Source:
http://www.sciencedaily.com/releases/2006/12/061207161049.htm
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