Drug Approved to Treat Nail Fungus Found to Delay
Chemo in Advanced Prostate Cancer
Itraconzole slows prostate cancer progression but
has potential of serious side effects
June
3, 2011 - The oral antifungal drug itraconazole, most
commonly used to treat nail fungus, may keep prostate cancer from
worsening and delay the need for chemotherapy in men with advanced
disease, according to new research from John Hopkins.
Currently, the drug is approved to treat fungal
infections in nails and other organs. Serious side effects can include
heart failure, and Johns Hopkins researchers caution that itraconazole
needs further study before it can be considered for prostate cancer
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Details of the finding, from a clinical trial led
by Johns Hopkins experts, are scheduled for presentation on Saturday,
June 4 at the 2011 American Society of Clinical Oncology (ASCO) annual
meeting.
Identified as a potential anticancer drug after
Hopkins scientists scoured a database of more than 3,000 FDA-approved
drugs, itraconazole appears to block tumor blood vessel growth - the
only drug in its class to do so - much like the anticancer drug
bevacizumab (Avastin).
The antifungal also disrupts a key
cancer-initiating biological pathway called Hedgehog. Laboratory testing
by Johns Hopkins scientist Jun Liu, Ph.D., has shown that human prostate
tumors implanted in mice shrink when treated with itraconazole.
"The most effective therapy we have right now for
metastatic prostate cancer is hormone therapy, and when it doesn't work,
the next step is usually chemotherapy," says Emmanuel Antonarakis, M.D.,
assistant professor of oncology at the Johns Hopkins Kimmel Cancer
Center. In a search for compounds that could put off chemotherapy, the
Johns Hopkins team turned to itraconazole.
For the study, patients with prostate cancer that
had spread to other organs and did not respond to hormone therapy were
randomly assigned to receive low or high doses of itraconazole.
Over 24 weeks of daily treatment with oral
itraconazole, the investigators tracked the length of time for each
patient's prostate cancer to worsen (called progression-free survival).
Evidence of worsening disease was measured by a 25 percent increase in
their blood level of prostate specific antigen (PSA), a marker for
prostate cancer.
Early in the trial, preliminary analysis of 17 men
receiving low doses of itraconazole showed that only two of them (11.8
percent) had stable or declining PSA. Because of the limited response,
no further men were given low doses of the drug.
However, 11 of 24 (48.4 percent) men taking high
doses of itraconazole had stable or declining PSA levels lasting at
least 24 weeks. In addition, nearly a third of men taking the high dose
had PSA reductions of 30 percent or more. Metastatic prostate cancer
patients receiving no treatment typically would worsen in eight to 12
weeks, according to Antonarakis.
The investigators also found that 12 of 14 men
taking high doses of itraconazole had lower levels of circulating tumor
cells present in their blood after therapy, compared with their baseline
levels.
Seven patients experienced side effects, including
low potassium, hypertension and fluid retention, but the problems were
resolved with potassium replacement pills, anti-hypertension drugs, and
diuretics.
"We also tested whether itraconazole acted as
hormone therapy by tracking levels of testosterone and DHEA (a
testosterone derivative) in the blood, and we found no reductions of
either testosterone or DHEA," says Antonarakis.
"This finding shows that itraconazole is not just
another hormone therapy, and has a unique mechanism of action."
Antonarakis and colleagues next plan to examine
blood and skin samples taken from study participants specifically to
look for levels of proteins linked to tumor blood vessel formation and
the Hedgehog pathway.
"With these results, we believe that high-dose
itraconazole is worth studying in a larger group of men with advanced
prostate cancer," adds Antonarakis.
The clinical trial was funded by the Department of
Defense (DoD) Prostate Cancer Research Program, the Commonwealth
Foundation for Cancer Research, the David H. Koch Charitable Foundation,
a 2009 American Society of Clinical Oncology (ASCO) Young Investigator
Award granted to Antonarakis, and the National Institutes of
Health/National Cancer Institute.
In addition to Antonarakis, other investigators
participating in the research on behalf of the Prostate Cancer Clinical
Trials Consortium included Amanda Blackford, Serina King, Anja Frost,
Seun Ajiboye, Sushant Kachhap, Michelle Rudek, and Michael Carducci from
Johns Hopkins; Elisabeth Heath from the Karmanos Cancer Institute; David
Smith from University of Michigan, Ann Arbor; and Dana Rathkopf and
Daniel Danila from Memorial Sloan Kettering Cancer Center.
Why is Itraconazole prescribed?
Itraconazole capsules are used to treat fungal
infections that begin in the lungs and can spread through the body.
Itraconazole capsules are also used to treat fungal infections of the
fingernails and/or toenails. Itraconazole oral solution is used to treat
yeast infections of the mouth and throat and suspected fungal infections
in patients with fever and certain other signs of infection.
Itraconazole is in a class of antifungals called triazoles. It works by
slowing the growth of fungi that cause infection.
Warning
Itraconazole can cause congestive heart failure
(condition in which the heart cannot pump enough blood through the
body). Tell your doctor if you have or have ever had heart failure; a
heart attack; an irregular heartbeat; any other type of heart disease;
lung, liver, or kidney disease; or any other serious health problem. If
you experience any of the following symptoms, stop taking itraconazole
and call your doctor immediately: shortness of breath; coughing up white
or pink phlegm; weakness; excessive tiredness; fast heartbeat; swelling
of the feet, ankles, or legs; and sudden weight gain.
Do not take cisapride (Propulsid), dofetilide (Tikosyn),
pimozide (Orap), or quinidine (Quinaglute, Quinidex, others), while
taking itraconazole. Taking these medications with itraconazole can
cause serious irregular heartbeat.
Talk to your doctor about the risks of taking
itraconazole.
>> More at
PubMed, U.S. National Library of Medicine
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