Figure 2.

Proposed outlines for the use of drug-resistance genes in genetic diseases and malignancy. (A) In vivo selection for genetic diseases: Conditioning should allow for minimal engraftment of genetically corrected stem cells and should minimize toxicity. In vivo selection should increase gene marking to therapeutic levels while minimizing toxicity. Slowly ascending doses of chemotherapy drugs have achieved selection with minimal toxicity in a canine model of MGMT-mediated in vivo selection. (B) Marrow protection for malignant disease. Pretransplantation conditioning should ensure engraftment of gene-modified cells and exert an antitumor effect. Chemotherapy after the reinfusion of gene-modified cells should balance hematopoietic toxicity, extrahematopoietic toxicity, and antitumor effect. A greater overall toxicity will be acceptable in cancer patients compared with the treatment of genetic diseases. The combined use of “designer-mutant” drug-resistance genes and pharmacologic inhibitors of the wild-type gene product will allow for selectively depriving the tumor of defense mechanisms against the cytotoxic drug, while sparing the genetically protected bone marrow.