RESEARCHERS FIND WAY TO MAKE ANTI-CANCER DRUG MORE EFFECTIVE
COLUMBUS, Ohio -- Pharmacy researcher Kenneth Chan is teaching an old drug new tricks. Chan and his colleagues have identified a way to improve the effectiveness of one of the oldest and most widely used anti-cancer drugs.
The drug -- cyclophosphamide -- dates back to the 1950s. It is used today to treat 6 million patients a year for malignancies such as Hodgkin's disease, leukemia, lymphoma, and breast and prostate cancer.
But cyclophosphamide has its problems: It is quickly broken down in the body, its effectiveness varies widely between patients, and it has significant side effects and toxicity.
"We believe we have found a way to reformulate the drug to make it even more effective and eliminate some of these problems," said Chan, professor of pharmacy and internal medicine at Ohio State University's Comprehensive Cancer Center. The researchers found that one of the chemicals produced when cyclophosphamide is broken down by the body -- phosphoramide mustard -- has the greatest anti-cancer activity. Reformulating the drug to use only the phosphoramide mustard
would eliminate the problem of differences between people in their ability to activate the drug. It would also solve the problem of cyclophosphamide's toxic side effects, Chan said.
The bad news is that phosphoramide mustard quickly breaks down in the body and is rapidly flushed away.
"We're trying to preserve the integrity of the drug and enhance it's stability by packing it into liposomes. Preliminary results from animal studies suggest that it will work," said Chan. Liposomes are microscopic spheres of lipid -- fat -- that are being tested for delivery of a variety of drugs.
The study, published in the December 15 issue of the journal Cancer Research, involved 12 patients who took cyclophosphamide. The researchers used blood samples from the patients to study the various intermediate chemicals produced when cyclophosphamide is activated in the body.
Little was known about these intermediates before, said Chan. "They degrade, fall apart, quickly. If you don't analyze them properly they just fly apart."
As part of this study, Chan and his colleagues developed new analytical methods that stabilized the intermediates and allowed them to be measured.
"This study provides a more critical assessment of the role of some of the intermediates," said Chan. "Our results tell us a lot about which ones are therapeutically important and which are not."
Cyclophosphamide belongs to class of anti-cancer drugs known as alkylating agents. They work by attaching to DNA. This prevents DNA from uncoiling, blocks cell division, and causes cell death.
In the body, the drug is converted first to one, then to other chemicals in a chain of reactions known as an activation pathway. In the course of activation, one of the intermediate chemicals reacts with DNA, but another ends up causing bleeding in the bladder, or hemorrhagic cystitis, the drug's most severe side effect.
The researchers used a chemical test to measure the alkylating activity of the intermediates: the greater the alkylating ability, the greater the anti-cancer ability.
They found that the activity was greatest for phosphoramide mustard.
That was good news. Phosphoramide mustard is produced at the end of the activation pathway. The chemical responsible for bleeding in the bladder is produced earlier in the pathway. Use of the phosphoramide mustard, therefore, would avoid this toxic chemical altogether.
"An important message from this work," said Chan, "is that by looking critically at an old drug, we can often find new information that will perhaps lead to developing a better drug."
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Contact: Kenneth Chan, (614) 292-5022
Written by Darrell E. Ward, (614) 292-8456