SEATTLE--Genetically modified hematopoietic cells are being used to protect healthy stem cells from toxic drugs in early clinical trials and, in cell lines, to sensitize cancer cells to toxic drugs and to induce leukemia cells to revert to a normal phenotype, Albert Deisseroth, MD, PhD, said at a symposium held in conjunction with the American Society of Hematology meeting. Dr. Deisseroth is associate director for clinical research, Yale University Cancer Center.
In one such protocol, using a retroviral vector, the Yale researchers transduce the human multidrug-resistance gene (MDR-1) into patient stem cells that have been purified via a monoclonal antibody column technique. These genetically altered cells are returned to the patient, who then receives paclitaxel(Drug information on paclitaxel) (Taxol) therapy.
Studies using this technique are now underway at the NIH, M.D. Anderson, and Columbia University, in nine ovarian cancer patients and nine breast cancer patients, Dr. Deisseroth said. Thus far, the studies have shown rapid recovery of hematopoietic function, and the cells that have repopulated the marrow do carry the transduced MDR-1 construct.
"We're in a position now," Dr. Deisseroth said, "to test whether post-transplant chemotherapy can select for genetically modified cells; in other words, whether the MDR-1-carrying cells will thrive after these patients are treated with Taxol, thus reducing the cytopenia that usually complicates chemotherapy. If so, the result would be chemoprotection."
Dr. Deisseroth also theorized that retroviral vectors in hematopoietic cells might be used to help overcome the problem of residual cancer cells contaminating transplanted marrow. The approach involves "chemosensitizing" the bone marrow cells, via genetic transduction, in such a way that the cancer cells are destroyed by chemotherapy while normal cells remain unharmed.
The Yale research team used an adenovirus vector linked to a transcription unit that codes for cytosine deaminase, a bacterial gene not present in mammalian cells. This enzyme is able to deaminate the innocuous drug 5-fluorocytosine (5-FC), converting it into the highly toxic drug, 5-fluorouracil (5-FU).
The key point of this system, Dr. Deisseroth said, is that the adenovirus vector binds avidly to an integrin receptor on neoplastic cells but does not bind avidly to early hematopoietic cells. "Thus, the vector has a specific tropism for the very cells we want to destroy," he said.