When a persistent, cancerous tumor starts to grow back after chemotherapy, it's often immune to all known drugs. But new research published in the current issue of Clinical Cancer Research indicates that a first strike with a certain class of chemicals can break down this resistance. If this strategy, tested in a petri dish, holds up in animal and human testing, it could become a one-two knockout punch for many cancers.
Tumors can become resistant to chemotherapy by turning on a cellular protein called P glycoprotein, which is believed to pump chemotherapeutic drugs out of the cell. Most cells make only small amounts of this pump protein, and they eventually succumb to the drug. But the few cells that can over-express the pump gene in response to the toxic attack will often survive, expelling any of several drugs.
Joshua Hamilton and his colleagues at Dartmouth Medical School in Hanover, New Hampshire, had been studying a class of chemotherapeutic agents that damage DNA by fusing its strands, preventing the cell from making proteins. In previous work, they had found that certain of these compounds such as mitomycin C attacked genes that turn on in response to their environment, such as the gene for P glycoprotein. To turn off the pump gene before any other toxic agent could be expelled, the researchers added mitomycin C to resistant liver tumor cells from rats. After waiting 24 hours for the existing pump proteins (and the mRNA that helps produce them) to degrade, they added a standard chemotherapy agent, called doxorubicin, that inhibits proper DNA replication. The pump action dropped by half, and doxorubicin became 5 times more effective at killing the resistant tumor cells.
"It's an interesting mechanism, and they should pursue it," says Martin Brown, a cancer biologist at Stanford University. Although the enhancement was less marked in four other kinds of tumor cells, Hamilton notes that the pump-busting mitomycin C can boost the effectiveness of several different chemotherapeutics. "It's my belief that we don't need better drugs, we need smarter ways to use the drugs we have," he says.