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Drug resistance does the trick

Creating chemotherapy-resistant stem cells could improve cancer treatment and overcome roadblocks to gene therapy, according to Kiem lab study

Jan. 22, 2004
Jesse Thompson

Jesse Thompson, research technician in Dr. Hans-Peter Kiem's lab, picks E. coli colonies from a Petri plate. The bacteria are used in one step of the experimental process to create improved tools and drug-resistance strategies for cancer chemotherapy and gene therapy.

Photo by Todd McNaught

Scientists in the Clinical Research Division have developed a treatment strategy that could improve chemotherapy as well as surmount obstacles to gene therapy, a technique holding promise for curing inherited diseases.

Dr. Hans-Peter Kiem and colleagues have engineered blood-forming stem cells to contain a drug-resistance gene, which they expect will provide the cells with a survival advantage in cancer patients undergoing high-dose chemotherapy. Such patients typically suffer many toxic side effects because the chemotherapy not only destroys cancer cells, but also the body's healthy blood stem cells. This can result in life-threatening infections and dangerously low blood counts.

The new method, which may spare patients from such complications, will be tested in clinical trials with brain-cancer patients at the University of Washington and the Seattle Cancer Care Alliance.

The researchers expect that the same strategy could be employed to boost the usefulness of gene therapy as a cure for variety of genetic disorders in humans. Gene therapy research aims to cure inherited diseases by introducing healthy versions of genes into stem cells that are infused into patients. The method's success has been limited in part by the inability to maintain large numbers of the therapeutic stem cells in patients. In a study published in the November issue of the Journal of Clinical Investigation, Kiem and colleagues have shown that use of the drug-resistance strategy in a canine model enabled the infused genetically modified stem cells to grow to levels higher than have ever been observed before.

"This is the first clear evidence that this technique works in a large animal model, which is an important demonstration before we begin clinical trials," Kiem said. "We expect that the method will allow us to give more intensive chemotherapy to patients with cancers that are treated with the drugs for which we have engineered resistance in stem cells, such as brain cancer and melanoma."

Co-authors of the paper included Kiem lab members Dr. Tobias Neff, postdoc and lead author; former postdoc Dr. Peter Horn; and technicians Laura Peterson, Bobbie Thomasson and Jesse Thompson. Dr. George Georges of the Clinical Research Division and colleagues at Cincinnati Children's Hospital Medical Center and the University of Freiburg, Germany, also took part in the study.

To conduct their experiments, the researchers introduced a drug-resistance gene into blood-forming-or hematopoietic-stem cells. The drug-resistance gene confers resistance to BCNU and temozolomide, two chemotherapy drugs that work by causing damage to DNA. Both drugs are highly toxic to hematopoietic stem cells, which often results in dangerously low blood counts. This side effect can prevent doctors from administering the drugs at their needed dosage or frequency, which can result in incomplete therapy for the patient.

Researchers found that the transfused genetically modified stem cells multiplied and successfully produced sufficient quantities of new blood- and immune-system cells essential for survival. When the scientists measured the numbers of one class of the cells known as granulocytes, they found that up to 98 percent of the cells had been produced from the drug-resistant stem cells. This indicates that the engineered cells are highly effective at repopulating the blood and immune system with new cells.

"This demonstrates that we can very efficiently select for the growth of these stem cells," Kiem said.

The technique, which was well tolerated and did not cause side effects, is also likely to prove useful for gene therapy. Because the therapeutic genes introduced into stem cells for gene therapy typically do not confer their own survival advantage in patients, researchers may be able to selectively encourage the growth of the therapeutic cells by using the drug-resistance trick.

Neff's study was performed with canine stem cells from tissue-matched littermates, which suggests that the strategy could also be used in patients who undergo stem-cell transplantation with tissue-matched sibling or unrelated donors. In particular, the new strategy may be useful with a milder form of the transplant procedure known as the mini-transplant. Mini-transplantation-also known as nonmyeloablative transplantation-involves treating a patient with drugs to suppress the immune response and minimal doses of radiation before donor stem cells are infused. If patients must undergo additional chemotherapy after the transplant, the drug-resistance strategy could help patients maintain their blood counts.

"By engineering the donor stem cells to be drug-resistant, we could protect the donor graft from the destructive effects of chemo often necessary to treat patients with progressive or recurrent disease after allogeneic stem-cell transplantation," Kiem said. The findings also reinforce the importance of studying animal models relevant to humans, since discoveries in mice often do not hold true for man. In a separate study published in the Dec. 15 issue of Blood, Horn, Kiem and colleagues found that different classes of hematopoietic stem cells repopulate the blood and immune systems of an experimental type of mice known as NOD/SCID mice and large animals.


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