Embargoed for Release 5 p.m. Eastern Time November 8, 1999
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Rob Levy
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NOVEL DRUG COMBINATION DESTROYS HUMAN TUMORS IN MICE BY
TARGETING KEY POINTS IN CELL DIVISION PROCESS, STUDY FINDS
b-lapachone and Taxol provide one-two punch to tumor cells
BOSTON -- For more than two decades, scientists have known that normal cells have a quality-control system that signals them to detect and repair genetic damage or commit suicide if that damage is irreparable. When this control system fails to function, cells carrying genetic mutations continue dividing unchecked and can eventually progress to cancer.
Now, in a new study published in the Nov. 9 issue of the Proceedings of the National Academy of Sciences, researchers at Dana-Farber Cancer Institute report that a two-drug therapy that artificially rebuilds the cell's quality-control system can completely destroy human tumor cells grown in laboratory animals.
"This work provides a model for the rational design of new generations of anti-cancer drugs and their combinations," says the study's lead author, Chiang J. Li, M.D., of Dana-Farber. "We've shown that drug combinations that act at different key points in the cycle of cell division are able to bring about cancer cell death."
The study adopts a novel approach to the problem of how to make cancer cells, which have lost the ability to either repair their damaged DNA or kill themselves, undergo "apoptosis," or cell suicide.
Cells normally divide in a series of carefully timed steps. After a brief stage called Gap1 (or G1), a cell copies the DNA in its chromosomes in a stage known as Synthesis (or S). After a second preparation period, called G2, the cell divides, and an identical set of chromosomes goes into each of the daughter cells in a stage called Mitosis (or M). (See Attached Visusal).
During each stage of division, cells normally pause to make sure the new set of chromosomes is identical to the old. If not, the process of division is put on hold while repairs are made. If the damage to the chromosome is too extensive to be repaired, the cell will commit suicide rather than pass flawed DNA on to its descendents. These pauses in cell division are known as checkpoints.
In cancer cells, the checkpoint at G1 fails to function, preventing the cell from dying.
Knowledge of the mechanics of cell division has inspired a variety of strategies for provoking suicide in cancer cells. Nearly two decades ago, for example, Dana-Farber's Arthur B. Pardee, Ph.D., senior author of the current paper, disrupted the G2 checkpoint in tumor cells - the theory being that cells that lack both the G1 and G2 checkpoints would accumulate so much genetic damage they would have no choice but to self-destruct.
In the new paper, Drs. Li, Pardee, Youzhi Li and their colleagues took a different approach. "Because tumor cells lack functioning checkpoints, we wanted to see what would happen if we treated the cells with drugs that would replace those checkpoints," said Chiang Li. "Would they arrest the process of cell division and cause the cells to die?"
The researchers decided to take this strategy one step further. Instead of targeting only one checkpoint, they would treat the cells with drugs that mimicked the function of several checkpoints, in the hope that this would produce so many conflicting signals within the cells that they would die.
The researchers settled on two drugs to test this concept: taxol, a well-known drug that serves as an M phase checkpoint, and b-lapachone, which acts as a G1 and S phase checkpoint. (b-lapachone is derived from the Pau D'arco tree, a South American plant whose leaves are used in several herbal medicines.)
They treated laboratory cultures of human tumor cells with taxol and b-lapachone both alone and in combination. When given alone, the drugs caused about half the tumor cells to die. The same was true when the cells were treated first with taxol then, 24 hours later, with b-lapachone.
But a different sequence of the drugs produced a highly dramatic result: "When we gave both drugs at the same time, or when b-lapachone was given 24 hours ahead of taxol, all the tumor cells died," Chiang Li says. The same result was obtained with a wide variety of tumor cells. "The sequence in which the drugs are given clearly has a major impact on the effectiveness of the treatment," Li continues.
The next step was to test the treatment on cancers in animals. Researchers grew human ovarian tumors in laboratory mice and treated them with the same combinations of taxol and b-lapachone as were tested in the cultures. The results were the same: in the animals treated with taxol or b-lapachone alone, or with taxol prior to b-lapachone, the tumors shrank by about half in both size and number. In the animals that received both drugs, or b-lapachone ahead of taxol, all the tumor masses disappeared, the mice's abdomens did not swell with liquid (a common problem in ovarian cancer), and the mice survived without complications.
"This demonstrates that these two drugs, given in the proper sequence, may represent a new therapy against human cancers," Chiang Li says. "More broadly, it demonstrates that drug combinations that target the cell cycle at critical points can bring about cell death. This provides a framework for developing new drugs that may work in the same way."
Li and his colleagues hope to begin a clinical trial that will test the therapy in human patients.
The researchers involved in this study include, Drs. Chiang J. Li, You-Zhi Li, Arthur B. Pardee, of Dana-Farber Cancer Institute and Harvard Medical School, and Dr. Antonio Pinto, of the Cidade University, Brazil.
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