Discoveries
Novel drug combination destroys human tumors by targeting key stages of cell division
Cancer cells have a glitch in their quality-control system: signals that normally prompt cells to repair genetic damage — or commit suicide if the damage is irreparable — fail to function, causing tumor cells to pass defective DNA on to their offspring. In a recent study, investigators at Dana-Farber reported that a two-drug therapy that artificially rebuilds the qualitycontrol system causes human tumors grown in laboratory animals to destroy themselves.
Study authors Arthur Pardee, Ph.D., (left) and Chiang Li, M.D., have caused human tumors grown in laboratory animals to destroy themselves after being treated with a special two-drug therapy.
"This work provides a new foundation for the rational design of anti-cancer drugs," says the study's lead author, Chiang Li, M.D., of the Department of Cancer Biology. "We've proved that drug combinations that act at key points in the cycle of cell division are able to bring about cancer cell death."
The study adopted 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," the process of cell suicide.
Cells normally divide in a series of stages during which their chromosomes are copied. In each phase, the cells normally pause to make sure the new set of chromosomes is identical to the old. If it isn't, the process of division is put on hold while repairs are made. If damage to the chromosome is too extensive to be repaired, the cell will commit suicide rather than pass flawed DNA on to its descendents. The pauses in division are known as checkpoints.
In the vast majority of cancer cells, a checkpoint known as G1 fails to function, preventing the cell from dying and causing it to bequeath flawed chromosomes to its offspring.
In their study, Li and senior author Arthur Pardee, Ph.D., decided to see what would happen if they treated cancer cells with drugs that take the place of several checkpoints. Their hope was that this would produce so many conflicting signals within the cells that they would die.
"This demonstrates that these two drugs, given in the proper sequence, may represent a new therapy against human cancers."
— Chiang Li, M.D.
They settled on two drugs: taxol and ß-lapachone. When they treated laboratory cultures of human tumor cells with taxol and ß-lapachone at the same time, or when ß-lapachone was given 24 hours ahead of taxol, all the tumor cells died. The same results were obtained with human ovarian tumors grown in laboratory mice.
"This demonstrates that these two drugs, given in the proper sequence, may represent a new therapy against human cancers," Li says. "More broadly, it demonstrates that drug combinations that target the cell cycle at critical points can bring about cell death."
