For decades, soldiers on the cancer front have dreamed of therapeutic agents that work like hired assassins-homing in on tumor cells and killing them without laying waste to innocent bystanders. Now there is hope that drugs combining aspects of both chemotherapy and radiation can treat certain cancers in just that way.One team of researchers explpring this approach, led by David Scheinberg, chief of leukemia services at Memorial Sloan-Kettering Cancer Center in New York, is testing such a drug on 20 leukemia patients who failed to respond to conventional chemotherapy. The drug consists of atoms of the radioactive isotope bismuth-213 attached to antibodies. Those, in turn, bind to a protein found on the surface of leukemia cells. When the bismuth-213 decays, it releases alpha-particle radiation that destroys the target cells.
Several hurdles had to be overcome during the 15 years required to develop the strategy. “First we had to find a suitable antibody that generated a minimal immune response,” Scheinberg says. The solution came in the form of a monoclonal antibody dubbed SmartM195, designed by computer at Protein Design Labs of Mountain View, Calif. A second obstacle was figuring out a way to attach the cancer-killing agent to the antibody. “You don’t want the radioactive atoms to fall off and end up someplace else like the liver where they can cause real damage,” Scheinberg adds. The developers met this challenge by employing a so-called “linker” molecule, called DTPA, that chemically binds the radioisotope to the antibody.
In the first clinical trial, the drug reached its target within five to ten minutes after being injected in patients. And the drug seems highly selective, delivering 30,000 to 50,000 times more radiation to leukemia cells than to healthy tissue, Scheinberg says. The potency and precision of killing is amazing, he adds. “It appears that a single bismuth atom can kill a cancer cell, which would make it the most potent agent I’m aware of.”
Trials have shown no evidence of acute toxicity or other major side effects caused by inadvertent damage to healthy cells. “If we can demonstrate significant [anti-cancer] activity without significant toxicity,” Scheinberg says, “we’ll select appropriate doses and try this out on a larger number of patients.”