TARGETING DNA GIVES POWERFUL CANCER DRUG EXTRA BOOST IN SHRINKING TUMORS
COLUMBUS, Ohio – New research suggests that combining the chemotherapy drug paclitaxel with very low doses of the HIV-fighting drug AZT may shrink or even eradicate certain types of cancer tumors.
Using both drugs in mice helped inhibit the enzyme telomerase, a component critical to the livelihood of some cancer cells. Telomerase helps to build and maintain telomeres – protective strands of DNA at each end of a chromosome.
Researchers found that the drugs work in tandem: paclitaxel essentially slices off telomeres from chromosomes, while AZT inhibits telomerase from repairing the damaged telomeres. If a cell’s chromosomes are not protected, that cell will eventually die.
“This gives us a new way of looking at cancer treatment,” said Jessie L-S Au, the study’s lead author and the Dorothy M. Davis chair of cancer research at Ohio State’s College of Medicine and Public Health. “We believe that one approach to fighting cancer is to maximize the effect of existing drugs that patients respond to.
“In this study, we found that a powerful chemotherapy drug did indeed work better when given an extra boost.”
The study appears in the current issue of the journal Cancer Research.
The extra boost came from AZT, a drug that’s part of a class of drugs called telomerase inhibitors. AZT is usually used to slow the spread of HIV infection throughout the body.
“The dose of AZT used is a fraction of the doses used to fight HIV – about 100 times,” said Au, who is also a Distinguished University Professor in Ohio State’s colleges of Pharmacy and Medicine and Public Health.
The paclitaxel-AZT combination led to a decrease in tumor size in mice given both drugs. Animals not treated with the combination showed up to a four-fold increase in tumor size.
While telomeres are found in any cell that contains genetic material, telomerase is seldom expressed in normal cells, so the chance of the drug combination damaging healthy cells is slim, Au said. However, about 90 percent of all human tumor cells express telomerase.
The researchers conducted two experiments – one on mice to determine if adding AZT improved the activity of paclitaxel, and the other on two types of laboratory-grown human cancer cells to see if targeting the tips of DNA was the reason for that improvement.
To see how paclitaxel and AZT would work together in the body, the researchers injected pharynx tumor cells into four groups of mice. One group received paclitaxel and AZT; another group received paclitaxel only; another group received AZT only; and a fourth group was treated with saline as a control. Some of the mice were euthanized at the end of the treatment and their tumors were removed for evaluation. To test how and if the drugs promoted longevity, the remaining mice were monitored for nearly three months or until they died.
Mice given the combined therapy lived an average of one week longer than the mice taking paclitaxel alone, and more than twice as long as mice given the saline control. Tumor size also decreased in mice given both paclitaxel and AZT, while average tumor size increased two to four times in the other groups, regardless of treatment.
“AZT provided the boost needed to start shrinking the tumor,” Au said of the mice taking both drugs. “Not only did the tumors get smaller in the mice given both drugs, these animals also had higher survival rates compared to the mice in the other three groups.”
The researchers also examined human pharynx tumor and osteosarcoma cells in the lab to determine the mechanisms that the paclitaxel-AZT combination used to attack cancer cells. Pharynx tumors express telomerase, while osteosarcoma cells don’t. The researchers wanted to see if AZT would enhance paclitaxel’s effect in telomerase-negative osteosarcoma cells. There was no effect.
“We wanted to show that this therapy is tumor-selective,” Au said. “In a real life situation, we would first have to determine if a tumor is dependent on telomerase. The drug combination will only work if a tumor expresses telomerase, and depends on telomerase for telomere maintenance.”
She added that she and her colleagues plan to one day test this new treatment concept in humans, but it will be at least several years before researchers know how effective the paclitaxel-AZT combination therapy is in humans.
The researchers discovered that paclitaxel cut off the tips of chromosomes in the laboratory-grown cancer cells. It did so very quickly, Au said, usually in less than an hour.
“Adding AZT increased this effect and boosted the anticancer activity of paclitaxel,” Au said. The study’s results showed telomerase inhibition in 40 to 100 percent of the pharynx tumor cells.
What’s key to this therapy is attacking telomeres and telomerase at the same time. Attacking telomerase alone is not sufficient because a cell may have pre-existing telomeres, which can keep a cell growing for several generations – even after their telomerase supply is cut off.
“We set out to prove that if paclitaxel’s effect could be enhanced by adding a telomerase inhibitor to the treatment regimen, then perhaps we could make chemotherapy more effective,” Au said. “Until now, there were unanswered questions as to how paclitaxel attacked a tumor cell, and how to boost the drug’s anticancer effect.”
The research was supported in part by a research grant from the National Cancer Institute.
Au conducted the study with Yiqun Mo, Yuebo Gan, SaeHeum Song, Jeffrey Johnston and Xiaodong Xiao, all with Ohio State’s college of pharmacy, and M. Guillaume Wientjes, with Ohio State’s college of pharmacy and college of medicine and public health.