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Genetically Altered Hematopoietic Cells Used in Transplant Research

Genetically Altered Hematopoietic Cells Used in Transplant Research

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 (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.

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