U researchers have developed a new medication to track down, invade and destroy tumor cells as they spread.
The new “bioconjugate” (joining) drug also contains a large molecule known as a copolymer to hold the drug inside cancer cells. It has proved effective in killing human breast, ovarian and colon tumor cells grown in the laboratory, according to a study published in the April issue of the journal, Pharmaceutical Research.
Other methods of targeting cancer cells, such as the magic bullets approach, are only partially successful because they target the outside of a cancer cell, but do not enter and destroy it.
“Those drugs go to the targeted cancer cells but they get squished out over the surface of the cell, so surrounding healthy cells get killed, too. We saw a lot of collateral damage,” said Glenn Prestwich, professor and chairman of medicinal chemistry at the College of Pharmacy and the study’s principal author.
The beauty of the new drug and delivery system is that researchers now have less of a “ricocheting” bullet and more of a “penetrating” bullet, he continued.
“The older drugs are called magic rubber bullets,” Prestwich said. “Ours are magic teflon bullets. They go right inside cells. This is a search-and-destroy method for cancer.”
Prestwich and his 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 soft tissue sarcomas, many cancers of the blood and solid tumors?particularly carcinoma of the breast, lung, thyroid and ovary,” said Jindrich Kopecek, distinguished professor and chairman of pharmaceutics and pharmaceutical chemistry at the U and a co-author of the study.
HA, 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 that cells stick to every place in your body, like a scaffold,” Prestwich said.
U researchers combined HA with doxorubicin. 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.
“In the new study, doxorubicin alone was most effective at killing cancer cells in culture,” Kopecek said. “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.”
In the second part of the study, doxorubicin was combined with a substance called HPMA copolymer, a small molecule attached to a large, chain-like molecule known as a polymer.
This combination, being tested on people in Europe now, allows cancer patients to be treated with doxorubicin even if they have developed resistance to it because the HPMA copolymer prevents the cancer cells from pumping out the doxorubicin. “The cell then acts like the roach motel of drugs,” Prestwich said.
In the third, most important portion of the study, U researchers added a third ingredient, HA, to serve as a targeting mechanism. This new triple combination was tested on cultured breast cancer cells and was 10 times more effective in killing them than just the first two ingredients used without HA were.
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. The triple combination also was tried on noncancerous mouse skin cells, and was not toxic to them.
While HA targets the cancer cell, the copolymer contains a peptide that delivers the drug combination like a “zip code” to a part of each cancer cell called the lysosome, which acts as the cell’s garbage can.
“When the [triple combination drug] binds to the lysosome of cancer cells, the copolymer zip code says, ‘Eat me,'” Prestwich said. “As a result, the copolymer is separated or ‘cleaved’ from the doxorubicin, which is then released into the tumor cell.”
To keep HA from sticking to healthy cells, researchers saturated most of the HA receptors of normal cells by feeding them chondroitin sulfate, a supplement available at any health food store.
“It’s like a sun block for the normal cells. Cancer cells only recognize HA, so they ignore the chondroitin sulfate,” Prestwich said. “Cancer cells are much more aggressive than normal cells and internalize or eat anything that has HA on it.”
After they dose the healthy cells with chondroitin sulfate, researchers introduce the new triple-combination drug, which the cancer cells eat and the normal cells ignore.
Animal and human studies will be needed to prove the value of the new approach. Tests on mice will start soon, but human tests are at least three years away.
Prestwich predicts the targeted combination medicine will prove to be 10 times more effective than the other combinations and expects his in vitro test results to carry over in clinical trials.
“HA also can be used as a targeting mechanism when combined with other anti cancer medications,” Prestwich said.
In unpublished research, the U 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. Researchers are seeing a complete breast cancer cure rate in their preliminary in vitro studies.