“We have found an effective way of containing and then delivering this highly potent element directly into cancer cells,” said study senior author David A. Scheinberg, M.D., Ph.D., Chief of MSKCC’s Leukemia Service and head of the Laboratory of Hematopoietic Cancer Immunochemistry at the Sloan-Kettering Institute.
The investigators tested the nanogenerators in cell culture in a variety of human cancer cell types: leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate. They found the nanogenerators could kill all these types of cancer cells at extremely low concentrations.
Dr. Scheinberg and colleagues also tested the treatment in two mouse models, one for prostate cancer and one for disseminated (widespread) lymphoma. Many of the animals had long-term survival, and all of them had their lives extended after a single treatment at a low dose. In addition, many of the mice with prostate cancer had their prostate-specific antigen (PSA) levels decrease to zero and most others had PSA levels that were reduced. PSA levels are a common measure of the presence of prostate cancer in humans.
The atom contained inside the nanogenerator is actinium-225. Actinium decays by giving off short-lived, high-energy alpha particles that blast through cancer cells and destroy their DNA and proteins. When actinium decays, it produces a series of three daughter atoms each of which gives off its own alpha particle. Each particle increases the chance that the cancer cell will be destroyed. “You get four times the punch from one atom,” Dr. Scheinberg said.
Targeting the generator to the inside of the cancer cells also increases the treatment’s effectiveness. “If the atom is sitting on the outside of the cell, the alpha particle can travel in any direction, and it kills the cell only a fraction of the time,” explained Michael McDevitt, Ph.D., the study’s lead author and a senior research scientist in Dr. Scheinberg’s lab. “If the generator is inside the cell, every particle will be effective.” In addition, keeping the generator inside the cell greatly reduces the possibility that the daughter atoms could float off and damage healthy cells.
Numerous developments in technology have made the new nanogenerators possible. “The idea of targeting radioactive metals to tumors was first demonstrated by us in 1981,” Dr. Scheinberg said. “So it’s taken us 20 years to get to this more effective and sophisticated method.” A large part of this advance was the development of antibodies that target various types of tumor cells in humans. In addition, researchers were able to identify an appropriate atom, actinium (which has long enough half-life to allow doctors time to administer the drug after it has been manufactured) and secure a supply of it from the Department of Energy -- because it is a by-product of waste from nuclear power plants and weapons. Finally, the researchers found a molecular cage, such as one developed by the Dow Chemical Company, that would hold the actinium atom.
Dr. Scheinberg and his team plan to file an application with the Food and Drug Administration to begin trials in humans sometime next year. He says leukemia will most likely be the first cancer the nanogenerators are tested on, because his team has the most experience targeting those types of tumors. Although the mice treated with the drug seemed to experience no toxic side effects, the true test of whether this will become an effective therapy will not be known until those human trials begin, Dr. Scheinberg noted.
This research was supported by the Doris Duke Charitable Foundation, the National Institutes of Health, the CaPCure Foundation, the Lymphoma Foundation, the Cure for Lymphoma Foundation, the Gabrielle Rich Foundation, and the Pepsico Foundation.
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