NEW YORK (Reuters Health) - Treatment with a genetically engineered mini-antibody, or “diabody,” laden with the beta-emitting radioisotope yttrium-90 significantly impedes the growth of established human breast tumor xenografts in mice, researchers report in the September 1st issue of Cancer Research.
“Overall, we are very pleased with the results, which show that antitumor diabody-based radioimmunotherapy can be an effective form of therapy,” Dr. Gregory P. Adams from the Fox Chase Cancer Center in Philadelphia said in a telephone interview with Reuters Health.
Since the mid-1980s, monoclonal antibodies have been used to target isotopes to tumor cells with the goal of getting more specific delivery of therapeutics, Dr. Adams explained. “This approach is hindered by the large size of monoclonal antibodies and their very nature, which is to remain in the blood a long time.”
Diabodies, which are one third the size of monoclonal antibodies, are better able to penetrate tumors and are cleared rapidly from circulation.
In mice, a single intravenous dose of the yttrium-90-labeled-C6.5KA diabody that specifically targets the HER2/neu human tumor-associated antigen significantly delayed the rate of growth of human breast tumor xenografts but fell short of inhibiting human ovarian cancer xenografts.
The disparate responses in the two different tumor models are not all that surprising, Dr. Adams said, and could be due to a number of factors including a higher rate of diabody uptake in mammary versus ovarian tumors as well as the presence of a normally functioning p53 tumor suppressor gene. The ovarian tumors cells lacked p53.
Dr. Adams admitted he’s “a little bit concerned about the renal toxicity.” Three mice studied 1 year after diabody therapy displayed increased serum creatinine levels, one exhibited early-stage renal disease, and another had severe kidney damage.
“As you make these molecules smaller and they are eliminated quickly, the neurotoxicity, which has been the hallmark of radioimmunotherapy, may not be the issue anymore, it may become renal toxicity,” Dr. Adams noted. “We may actually head toward iodine-131 as the therapeutic agent because that will not stay in the kidney,” he said.
His team has now completed additional studies using alpha-emitting radioisotopes and the results are even more promising. “In a study we’ve repeated twice now, 1 year after therapy, we’ve gotten about three complete responders out of five treated mice -- with no toxicity.”
Source: Cancer Res 2004;64:6200-6206. [ Google search on this article ]
MeSH Headings:Animal Diseases: Disease Models, Animal: DNA, Recombinant: Drug Toxicity: Genetic Vectors: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
