Drug-resistance gene saves mouse marrow.

Drug-resistance gene saves mouse marrow

Most people don't talk about their p-glycoproteins, but everybody's got them. Scattered upon the surfaces of cells in the colon, liver, kidneys and a few other organs, these proteins act like microscopic sump pumps, bailing out the occasional poisonous molecule absorbed by these cells from food.

Unfortunately, many tumor cells also sport these pumps, which grant them the ability to spit out potent anticancer drugs before the treatments have a chance to work. While higher drug doses or longer treatment periods could probably overcome the cells' bailing capacity, such intense regimens have a life-threatening side effect: They can wipe out the bone marrow, birtplace of oxygen-carrying red blood cells and immune-enhancing white cells.

Michael Gottesman and Ira Pastan of the National Cancer Institute (NCI) in Bethesda, Md., now say they have successfully spliced the human p-glycoprotein gene into mouse embryos to make strains of mice whose marrow cells can resist a wide variety of anticancer drugs. The accomplishment provides a convenient living model for analyzing this mechanism of chemotherapy resistance and for designing and testing potentially "irresistible" drugs that could dismantle or bypass the pumps. The work also hints of a future in which genetic engineers might splice the p-glycoprotein gene into cancer patients' bone marrow cells, thus affording these cells protection during the course of intensive chemotherapy, the researchers say.

One strain of the altered mice expressed the human gene only in their bone marrow cells, Gottesman reported in Tokyo this week at the 13th Bristol-Myers Squibb Symposium on Cancer Research. Experiments in vivo indicate the marrow cells survive chemotherapy treatments that would decimate normal mouse marrow. In cell cultures, the researchers have also managed to switch the transplanted gene on and off at will, Gottesman told SCIENCE NEWS. That suggests scientists may someday gain enough control over the gene to regulate its activity differently in different tissues, Pastan adds.

Drug designers may be the first to make use of the new mouse model, but cancer patients might ultimately derive lifesaving benefits from p-glycoprotein genes inserted directly into their marrow cells. Such gene therapy "may seem a little science-fictiony, but we take it seriously," Pastan says.