Utah scientists have developed a new combination of drugs that help target and destroy cancer cells without killing healthy cells.
This new drug combination also attacks the cancer cells as they spread or metastasize.
News Specialist Shelley Osterloh explains.
U of U researchers have found a way to better deliver cancer killing drugs to cancer cells.
By combining a chemotherapy drug with a sugar that normally helps cancer move through the human body, University of Utah Researchers developed a new medication to track down, invade and destroy tumor cells as they spread or metastasize.
Doxorubicin is a chemotherapy drug that is widely used to treat tumors of the breast, lung, thyroid and ovary.
But unfortunately, it also kills other fast growing healthy cells.
The new piggyback drug contains a copolymer that holds the cancer killing drug inside cancer cells -- and doesn't allow it to escape to kill healthy ones.
Glenn D. Prestwich, Ph.D/Univ. of Utah Medicinal Chemistry: MAKES IT SO THE DRUG GOES INTO THE CELL, BUT CAN'T BE GOTTEN OUT. SO EVEN A DRUG RESISTANT CELL CAN BE KILLED BY THIS STUFF. SO IT REALLY ALREADY ADDS AN ADVANTAGE TO THE DRUG BECAUSE YOU CAN USE IT AT LOWER TOXICITY, LOWER DOSES AND GET IT INTO CELLS THAT YOU COULDN'T BEFORE YOU MADE THE NEW COMBINATION.
The third ingredient is hyaluronic acid --- or H.A. It's a natural substance found in human cartilage that helps cells stick to each other, grow and migrate.
It sticks or binds to receptors on cells, and since cancer cells, especially ones that are spreading or metastasizing, have many more H.A. receptors, the piggyback drug is drawn to those hard to find cancer cells. It is a seek and destroy strategy.
Glenn D. Prestwich/Ph.D/U of U Medicinal Chemistry: THE IDEA IS TO FIND THOSE SMALL POPULATIONS OF SMALL METASTASES, METISTATIC CELLS AND KILL THEM BEFORE THEY HAVE A CHANCE TO MAKE A NEW TUMOR, AND THEN TAKE A PERSON WHO HAS GONE INTO REMISSION AFTER ONE ROUND OF CHEMO THERAPY, AND PREVENTING THAT PERSON FROM HAVING A REOCCURRENCE OF THE CANCER.
At least in the lab, this new piggyback combination appears to more effectively target and destroy cancer cells, even those tough to find cancer cells that are metastasizing.
Human tests on this triple piggyback drug are at least three years away, but tests on mice will begin soon.
By combining a chemotherapy drug with a sugar that normally helps cancer move
through the human body, University of Utah researchers developed a new medication to track
down, invade and destroy tumor cells as they spread or metastasize.
The new "bioconjugate" drug - which also contains a large molecule known as a copolymer to hold
the drug inside cancer cells - proved effective at killing human breast, ovarian and colon tumor
cells grown in laboratory glassware, according to a study published in the April issue of the journal
Pharmaceutical Research.
Some other methods of targeting cancer cells - such as using monoclonal antibodies as so-called
"magic bullets" - failed because they target the outside of a cancer cell but do not enter and
destroy it.
"They are magic rubber bullets" said Glenn D. Prestwich, principal author of the new study and
professor and chair of medicinal chemistry at the University of Utah College of Pharmacy. In
contrast, "ours are magic Teflon bullets. They go right inside cells. … For cancer that is
metastasizing, this is a search-and-destroy method."
"It's a new way of targeting anticancer drugs to cells," said Jindrich "Henry" Kopecek, a co-author
who is a distinguished professor and chair of pharmaceutics and pharmaceutical chemistry at the
university.
Prestwich said that while some other methods of targeting chemotherapy at cancer cells also
show promise, "you need to have an arsenal of weapons, not just a single weapon," to fight
cancer.
In their study, Prestwich, Kopecek and colleagues tested various combinations of the anticancer
drug doxorubicin with a polymer and a sugar known as HA or hyaluronic acid.
Doxorubicin is administered as an intravenous drip to treat a wide variety of solid tumors -
particularly carcinoma of the breast, lung, thyroid and ovary - soft tissue sarcomas and many
cancers of the blood, Kopecek said.
HA - which is found in human cartilage - is involved in helping cells stick to each other, grow and
migrate. HA sticks or "binds" to certain "receptors" on cells.
"HA is part of the extracellular matrix - the goop that cells stick to everyplace in your body, like a
scaffold," Prestwich said.
There are elevated levels of HA receptors on cells for many tumors, including breast, ovarian,
colon and stomach cancers and leukemia. That helps the cancers spread or metastasize.
"Tumors cells use it to slime their way out of the tumor and slime their way through the blood,"
Prestwich said. "They use the receptors to reinvade elsewhere in the body."
The Utah researchers tried to turn the tables on human cancer cells by combining HA with
doxorubicin. So when the tumor cells bind to the HA, they "suck up" the anticancer drug, and
"that releases the drug in the tumor cell but not anywhere else," Prestwich said.
In the new study, doxorubicin alone was most effective at killing cancer cells in culture. But real
patients can only tolerate a limited amount of the drug because it is toxic to other cells, such as
heart cells, and can cause heart attacks, Kopecek said.
In the second part of the study, doxorubicin was combined with a substance called HPMA
copolymer, which is a small molecule attached to a large chain-like molecule known as a
polymer. The combination is being tested on people in Europe, Kopecek said. The combination
allows cancer patients to be treated with doxorubicin even if they have developed resistance to it.
That is because the HPMA copolymer prevents the cancer cells from pumping out the
doxorubicin, thus acting "like the roach motel of drugs," Prestwich quipped.
But the combination of the copolymer and doxorubicin is not selectively delivered to tumor cells,
so it still can damage any rapidly dividing non-cancer cell such as bone marrow cells. So in the
third and key portion of the new study, the Utah researchers added a third ingredient - hyaluronic
acid or HA - to serve as a targeting mechanism.
The triple combination of doxorubicin, HPMA copolymer and HA was tested on cultured breast
cancer cells and was 10 times more effective in killing them than when just the first two
ingredients were used without the HA to track down and target the tumor cells, Prestwich said.
Recent results show the triple combination is 50 times more effective in killing prostate cancer
cells, although that finding is not part of the new study, he added.
The triple combination also was tried on noncancerous mouse skin cells, and was not toxic to
them.
Prestwich said that while the HA targets the cancer cell, the copolymer contains a peptide that,
like a zip code, delivers the drug combination to part of each cancer cell called the lysosome,
which acts as the cell's garbage can.
When the doxorubicin-copolymer-HA combination binds to the lysosome of a cancer cells, the
copolymer "zip code says 'Eat me!'" Prestwich said. As a result, the copolymer is separated or
"cleaved" from the doxorubicin, which then is released into the tumor cell.
The researchers confirmed tumor cells took up the doxorubicin-copolymer-HA combination by
shining purple light on the cells. Doxorubicin within the cells absorbed the light, then re-emitted it
as fluorescent blue light observed by the scientists.
While animal and then human studies will be needed to prove the value of the new approach, the
newly published study "is a nice first step," Prestwich said. "It shows that you can get the drug
into cancer cells and kill them, and at the same dose it doesn't go into regular cells and it doesn't
affect them."
He said human tests of the triple combination are at least three years away, but tests on mice will
start much sooner.
Nevertheless, he predicted the targeted combination medicine "should be 10 times more effective"
than the combination of doxorubicin with the copolymer only.
The doxorubicin-copolymer combination - without the HA targeting mechanism - has completed
human safety trials in Europe and soon will complete initial tests of efficacy in dozens of patients.
HA also can be used as a targeting mechanism when combined with other anti-cancer
medications, Prestwich said. In unpublished research, the Utah scientists used HA as a way to
target taxol to breast cancer cells. The technique reduced and even eliminated the cancer in mice
with human tumor cells, Prestwich said. Taxol now is injected intravenously in a cream-like
substance that can cause severe allergic reactions, he added. The HA-taxol combination is
water-soluble, so it can be administered by an intravenous drip.
Prestwich and Kopecek were assisted in the new study by Yi Luo, a Utah medicinal chemist now
working at Vertex Corp. in Cambridge, Mass.; Nicole Bernshaw, a technician at the University of
Utah Center for Cell Signaling; and Zheng-Rong Lu, an assistant professor of pharmaceutics and
pharmaceutical chemistry.
