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Shielding the mother cells
By Bijal P. Trivedi

Recurring testicular and ovarian tumors could be attacked more aggressively with toxic chemotherapeutic agents if other healthy cells were first given some sort of protection, according to the preliminary results of a Phase I trial published in this month's issue of Nature Medicine.

A protein pumps the toxic drugs out of the healthy cells

Rafat Abonour, a bone marrow transplant physician at the Indiana University School of Medicine, in Indianapolis, is arming bone marrow stem cells with a drug resistance gene to protect them against the toxic effects of the anti-tumor drugs.

The human multi-drug resistance 1 (MDR-1) gene provides some protection by making a protein that pumps the toxic chemotherapeutic drugs out of the healthy stem cells.

Abonour's approach requires taking bone marrow stem cells from patients, introducing the new MDR-1 gene using a virus as the delivery vehicle, and putting the stem cells back into the patient. When the patient receives high doses of etoposide, a chemotherapy drug, unmodified stem cells are destroyed, but the fortified cells survive and repopulate the body with healthy new blood cells that also carry the MDR-1 gene. "The chemotherapy should be selecting the resistant cells," says Abonour. That is the theory.

However, while Abonour and his colleagues were particularly successful in delivering MDR-1 into the stem cells—25 percent of the cells incorporated the new gene—the patients were not able to tolerate the chemotherapy as well as anticipated.

"We expected that the unmodified cells would be destroyed by the chemotherapy and the stem cells with the MDR-1 would survive and expand the population quickly," said Abonour. But when samples of bone marrow were examined one year after the transplant only 5 to 15 percent contained the MDR-1 gene, and of these only 15 percent seemed to be making a version of the protein pump that actually worked.

Abonour is now attempting to modify the MDR-1 gene so that it consistently produces a functional protein. Further work also needs to be done to ensure that modified hematopoietic stem cells are still able to produce the complete range of blood cells.

Of the 11 patients who received the modified stem cells, eight have been followed for almost three years and have not suffered any adverse side effects from the virus-modified cells. "Before progressing to Phase II clinical trials, [where the clinical value of the technique is assessed] we need to see whether this technique is still safe when patients receive a higher number of modified cells," says Abonour.

Abonour is also investigating other drug resistance genes that could be used with a different range of chemotherapeutic agents.

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Abonour, R. et al. Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells. Nat Med 6, 652-658 (June 2000).

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