Transfer of drug resistance genes into hematopoietic progenitors to improve chemotherapy tolerance

Abstract

A number of drug resistance genes have been identified that may be useful in gene therapy approaches to ameliorate chemotherapy toxicity. Hematopoietic tissue is the most suitable target for drug resistance gene therapy because myelosuppression is the dose-limiting toxicity of the many chemotherapeutic agents. Recent studies have shown that murine and human hematopoietic progenitors can be transduced ex vivo using retroviral vectors to overexpress P-glycoprotein, dihydrofolate reductase, and O6-alkylguanine DNA alkyltransferase. In all instances, gene transfer results in significant drug resistance in hematopoietic progenitors both in vitro and in vivo. Clinical trials are underway to evaluate the role of MDR-1 gene therapy in amelioration of chemotherapy induced myelosuppression. Other genes being examined for their potential to transfer drug resistance to hematopoietic cells include genes encoding aldehyde dehydrogenase, nucleotide excision repair proteins, multidrug resistant protein, and superoxide dismutase. As a group these proteins could confer significant levels of chemotherapy drug resistance to bone marrow cells. When compared with other somatic gene therapy approaches, drug resistance gene therapy has the aim of protecting normal cells and preventing toxicity. In addition many of these genes could be used to select for cells carrying the drug resistance gene as well as cotransduced therapeutic gene. Thus, gene transfer of drug resistance genes will have broad applications in the field of gene therapy as well as in protecting hematopoietic cells from chemotherapy toxicity.