Contacts:
Akhouri Sinha, Ph.D., (612) 725-2000, X2846; (504) 525-9444 (New Orleans, March 28-April 1) Press Room, Morial Convention Center, (504) 670-7020 (March 27-April 1) Deane Morrison, University News Service, (612) 624-2346, [email protected]
Prostate Cancer Treatment From U of Minnesota Works in Mice; Researchers Aim for Clinical Trials in Fall
A prostate cancer treatment that kills cancer cells while largely sparing healthy organs has been successfully tested in mice and will be ready for clinical trials this fall if approved by the Food and Drug Administration, according to University of Minnesota researchers who devised the treatment.
Lead researcher Akhouri Sinha said the treatment holds promise for controlling the most common and lethal cancer afflicting men over 50 in the United States, a disease that annually claims about 45,000 lives in this country alone. The work will be presented in two parts, at 8 a.m. Sunday, March 29, and at 10 a.m. Wednesday, April 1, during the American Association for Cancer Research meeting at the Ernest N. Morial Convention Center in New Orleans.
Sinha, a professor of genetics and cell biology who also holds an appointment at the Veterans Affairs Medical Center (VAMC) in Minneapolis, said that longer life spans mean rising numbers of prostate cancer patients in the United States and other developed countries. Often symptomless, the cancer can metastasize before it's diagnosed. Sinha said his treatment is a step toward the day when prostate cancer can be controlled without surgery, which, even if successful, can cause impotence. Two years ago Sinha and colleagues demonstrated that the treatment worked against prostate cancer cells in culture. The mouse study was the next necessary step before clinical trials can begin.
"I think we can kill most of the cancer cells in two or three doses, at least in the mouse experimental model," said Sinha. "But to be sure it works in humans, we need clinical trials."
The problem with most anti-cancer drugs is that they work against any tissue whose cells are continuously growing, dividing and being replaced, whether cancerous or not. Thus, the drugs kill actively dividing cells in the lungs, intestinal lining, kidneys, hair follicles and other organs, often with severe side effects. Other approaches, such as treatment with antibodies, have failed because antibodies alone can't kill cells. What is needed, said Sinha, is a way to specifically target cancer cells so that drug dosages can be raised enough to control the cancer without sickening or killing the patient.
The new treatment takes advantage of the fact that most prostate cancer cells produce a protein, prostate specific antigen (PSA), that is unique to prostate cells. PSA is released into the bloodstream, and abnormally high levels are often the first sign of prostate cancer. But PSA is also found on the outer membranes of prostate cells and prostate cancer cells.
Taking advantage of this, Sinha and his team put together a compound that consists of two parts. One is an antibody that zeroes in on PSA-producing cancer cells. Connected to the antibody is a potent anti-cancer drug. The antibody attaches to molecules of PSA, causing the cell to "swallow" the antibody, drug and all. Once inside the cell, the compound is split by enzymes; this frees the drug to kill the cancer cell.
To test the system in animals, the researchers injected human prostate cancer cells under the belly skin of nude mice, a strain that lacks both hair and a functional immune system--an ideal environment for growing cancer cells. After the cancer had grown for about six weeks, the researchers injected the antibody-drug complex through the tail vein of the mouse. They then traced the complex as it travelled through the animals' organs and into the cancerous tumors.
They found that the complex accumulated steadily in the tumors, reaching a peak concentration after 24 hours and maintaining reduced, but still high, levels for up to five days--the duration of the study. That is much longer than the 18 hours of exposure required to kill cells, Sinha said. But the compound followed a different odyssey through nontargeted organs, namely kidney, liver and spleen. The compound accumulated briefly in those organs, but levels began to drop after an hour. After three or four hours, more than 90 percent of the compound had disappeared from the mouse organs but continued to accumulate in tumors. The researchers also found that the treatment killed tumor cells and suppressed their ability to grow and divide but caused no significant cell death or suppression in liver, kidney or spleen.
"We believe this treatment will greatly decrease damaging effects of the therapy to unrelated organs while decreasing morbidity and mortality in prostate cancer patients," Sinha said.
While no drug can be expected to kill every tumor cell, Sinha said that cells not directly killed by the treatment--including the 20 percent or so of prostate cancer cells that produce no PSA--can die if large numbers of neighboring tumor cells die.
"If we kill 80 percent of the cancer cells, we can take care of the rest by utilizing another drug," Sinha said.
The work was carried out at the Minneapolis VAMC. The other researchers were Pratap Reddy, a urologist at the VAMC; Barry Quast, Sheila Schemm and Nathanael Pederson of the university's genetics and cell biology department and the VAMC; and Michael Wilson of the university's laboratory medicine and pathology department and the VAMC. It was supported by the Minnesota Medical Foundation, the U.S. Public Health Service and the VAMC Research Service. If approved, clinical trials will be conducted by urologists at the university and the VAMC.
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