German researchers set out to outwit cancer tumor cells that have become resistant to chemotherapy or radiation therapy and ended up expanding therapeutic applications of radionuclides in fighting leukemia. This research was released at SNM’s 53rd Annual Meeting this week in San Diego.
“We have found that labelling the antibody CD45 with the alpha-emitter Bi-213 breaks resistance to radiation therapy and chemotherapy in leukemia cells by overcoming DNA-repair, which plays an important role in resistance,” said Claudia Friesen, group leader of the laboratory of molecular biology in the nuclear medicine department at the University Ulm in Germany. “We provided the molecular requirements for overcoming this resistance and for alpha particles–induced cell killing,” added the co-author of “Overcoming Chemoresistance and Radioresistance in Leukemia Cells Using Bi-213 Labeled Anti-CD45 Monoclonal Antibody.” She noted, “Targeted alpha particle radioimmunotherapy increases the dose to leukemia cells by two orders of magnitude and causes cell kill of single-targeted leukemia cells—all while sparing non-target tissues from detrimental radiation effects.” With the group’s approach, “therapeutic efficiency is increased and non-specific toxicity to normal organs and tissues is considerably decreased,” she explained.
“New options are needed to improve therapeutic success in the treatment of cancer, especially since tumors’ resistance to chemotherapy or radiation therapy is one of the primary causes of failure in treating the disease,” said Friesen. “Attempts to improve the results of chemotherapy and radiotherapy by increasing the total radiation absorbed dose, by increasing the concentration of chemotherapeutic drugs or by changing chemotherapeutic drugs have been only partially successful,” she noted.
“The targeted alpha particle therapy is much more potent than targeted beta particle therapy or external radiation therapy,” said Friesen. Low doses of alpha particles cause a prompt and complete cell kill in sensitive and resistant tumor cells, researchers discovered. “Our work considerably expands therapeutic options for therapeutically applied radionuclides,” she explained. “This technique will have a wide application in many solid tumors, using suitable peptides as carriers of alpha-emitting radionuclides,” she continued.
“Understanding the molecular mechanisms of sensitivity and/or resistance of tumor cells to radiation and chemotherapeutic drugs is crucial and fundamental for the development of novel treatment options in leukemia and solid tumor therapy. It provides the foundation for the discovery of novel anticancer compounds and the development of methods to sensitize previously resistant tumor cells to anti-cancer therapy,” said Friesen.
Researchers will now “focus on identification of novel molecular targets using gene expression technologies and high-throughput techniques for synthesis and selection of high-affinity peptides as carriers of radioisotopes both for diagnostic imaging and targeted internal radiotherapy,” said Friesen, who noted that the first clinical trial will begin soon.
Abstract: C. Friesen, B. Koop, G. Glatting and S.N. Reske, Nuclear Medicine, University Ulm, Germany; K..M. Debatin, Children’s Hospital, University Ulm, Germany; K. Schwarz, Transfusion Medicine, University Ulm, Germany; and A. Morgenstern and C. Apostolidis, Institution for Transurane, Karlsruhe, Germany, “Overcoming Chemoresistance and Radioresistance in Leukemia Cells Using Bi-213 Labeled Anti-CD45 Monoclonal Antibody,” SNM’s 53rd Annual Meeting, June 3–7, 2006, Scientific Paper 125.