La Jolla Team Has Designed Promising Cancer Fighter
A team of La Jolla scientists will report today that it has designed and synthesized a new class of anti-cancer compounds that appear more potent than other chemotherapies, including the much-touted experimental drug taxol.
The molecules, called synthetic enediynes, demonstrated a remarkable ability to target and destroy cancer cells without harming healthy cells, the researchers say in today’s issue of Science magazine.
“We know we have something very hot here,” said K. C. Nicolaou, the lead author of the study and chairman of the chemistry department at Scripps Research Institute.
Nicolaou cautioned that further fine-tuning will be necessary before the compounds can be tested in patients, which he and other scientists predict will occur within two years.
The molecules work by creating highly reactive chemicals called radicals that glom onto the cancer cell’s DNA, or the cell’s genetic headquarters. After they attach themselves, they break the DNA into pieces, stopping the cell from replicating and leading to tumor regression, said Nicolaou, who is also a UC San Diego professor of chemistry.
“Provided their selectivity against tumor cells versus normal cells can be maintained and enhanced in animal models and humans, these molecules may emerge as powerful drugs against cancer,” the scientists wrote.
Indeed, the ability of enediynes (pronounced een-dye-ines) to zero in on a cancer cell, demolishing its genetic headquarters, provides new strategies for anti-cancer drugs, some researchers say.
“What’s exciting is that enediynes can be quite selective. One can start to think about a specificity with enediynes that is not available to classical DNA-targeting drugs,” said Stuart Schriber, professor of chemistry at Harvard University.
“Nicolaou has been a leader in demonstrating innovative new avenues. He has demonstrated that we can take the basic principles of selectivity and reactivity of naturally occurring enediynes, go into the lab, and design new ones from scratch. He has really expanded the arsenal.”
Based on preliminary tests conducted in mice and in petri dish cultures, synthetic enediynes appear to have low toxicity, a quality that would make them easier for the body to tolerate, Nicolaou said.
Enediynes also seem to be effective against a broad range of cancers including skin, colon, ovarian, lung, pancreatic and leukemia, said Wolfgang Wrasidlo, an author of the study and head of Scripps’ drug discovery unit.
In fact, enediynes appear to act on more cancers, and act with more selectivity and potency than the experimental drug taxol, which has recently dominated the center stage of new anti-cancer drugs, he said.
During their study, the scientists tested standard anti-cancer agents and synthetic enediynes to see what quantity of each was needed to destroy half of the leukemia cancer cells in a petri dish within a 72-hour period.
When they compared the synthetic enediyne to five other anti-cancer agents, including taxol, they found that it was anywhere from 100 to 100,000 times more potent than the other agents tested, according to the study.
“This is very, very promising. We see some exceptional results,” said Wrasidlo, who added that the synthetic version also seemed to be more effective in battling drug-resistant cancers.
Each enediyne molecule is equipped with the equivalent of a molecular warhead, a delivery system, and a triggering device that initiates the severing of DNA strands.
The synthetic enediyne and the cancer cell are drawn together in a chemical mutual attraction. Once the enediyne enters the cancer cell, it is trapped. In the process of destroying the cancer cell, it also destroys itself.
Nicolaou likens the process to a molecular version of a Trojan horse: “The cell has no idea what it’s getting. The molecules enter the cell intact and, upon activation, destroy the genetic material via both single- and double-strand DNA cuts.”
Scientists, however, are still uncertain about what triggers the enediynes’ warhead--a phenomenon they will continue to investigate.
The new molecules are synthetic versions of compounds found in bacteria collected from soil cultures. The natural versions, which are highly toxic, were discovered in 1987 by pharmaceutical industry researchers.
When Nicolaou first saw the natural version, he was incredulous.
“I couldn’t believe my eyes. The molecular architecture was very novel,” he recalled. “It looked so diabolical.”
Though potent in their anti-cancer activity, the naturally occurring molecules fail to distinguish between healthy cells and tumor cells. So Nicolaou and others set about trying to create synthetic versions.
“The natural enediyne products isolated thus far are all potent anti-tumor agents. However, toxicity can be a serious problem, and the question is whether the two effects can be divorced,” said Andrew Meyers, an associate professor of chemistry at California Institute of Technology who conducts research in the field.
Nicolaou believed it was possible to create a safe enediyne, and he began focusing on dynemicin A--one of the four enediynes produced naturally--because it was “the easiest to make.”
In the synthetic version, Nicolaou and his colleagues modified the molecular warhead and triggering device. They also designed the molecule so that it had tethering devices that would allow them to attach other chemical groups to aid in the delivery of the molecule.
Basically, they wanted to mimic--as well as tame--the naturally occurring version and create a synthetic one that could be produced in a laboratory in large quantities at reasonable cost. It appears that the team did just that--if not more.
“We got more than we bargained for,” Nicolaou said. “We didn’t expect the remarkable selectivity.”
Dr. Lawrence Piro, director of the Green Cancer Center at Scripps, said preliminary tests were “extremely encouraging.”
“This drug looks as good as a new cancer drug can look,” Piro said. “We cannot see any impediment to getting this to people.”
In the next phase of research, Nicolaou will try attaching the synthetic enediynes to various “delivery systems,” such as specific antibodies or steroids--in an effort to further hone the enediynes’ ability to target a cancer cell.
The team also will continue to try to unlock the mystery of why the enediynes work as they do. The researchers have three possible explanations. It could be that tumor cells contain certain factors--such as proteins or enzymes--that normal cells do not contain. These enzymes may trigger the enediyne reaction, they say.
Or, it could be that tumor cells have a different wall structure and that the enediynes are more able to penetrate these cell walls--rather than the membranes of normal cells.
The final possibility is that cancer cells are unable to repair the damage wreaked by the synthetic molecules, while healthy cells can.
“We will persist,” Nicolaou vowed, “until we succeed.”
