Serial transplantation shows that early hematopoietic precursor cells are transduced by MDR-1 retroviral vector in a mouse gene therapy model.
The administration of high and repeated doses of chemotherapy has been hampered by the bone marrow toxicity imposed by these drugs. This obstacle can be circumvented by the introduction of chemotherapy resistance genes into the normal marrow cells, which are then transplanted back into the patient. To show that this approach can improve our ability to safely deliver high doses of chemotherapy, we used an animal model system to transplant bone marrow cells which have been transduced with a safety-modified retrovirus containing human multiple-drug resistance (MDR-1) cDNA into lethally irradiated mice. These studies produced mice whose bone marrow and peripheral blood displayed an increased level of MDR-1 expression and resistance to the myelotoxic side effects of Taxol. To determine whether sufficient numbers of early hematopoietic precursor cells were transduced with the MDR-1 retrovirus so that durable Taxol-resistant hematopoiesis would result, we serially transplanted the modified bone marrow cells into each of six successive cohorts of BALB/c mice. Taxol-resistant hematopoiesis with little or no myelosuppression was observed in all six of the cohorts. These data suggest that very early precursor cells were transduced by the vector. This animal model may be of use in the development of genetic therapy programs which use bone marrow to introduce therapeutic molecules into the systemic circulation, since it permits in vivo selection of genetically modified hematopoietic progenitor cells. Furthermore, the retroviral vector system we have used could have an immediate impact in the clinical setting, where it can protect patients from the myelosuppressive side effects of Taxol in advanced stages of human epithelial cancers.
Hanania
E G
EG
Department of Hematology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Deisseroth
A B
AB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells; D003673:Defective Viruses / Q000235:genetics*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008979:Moloney murine leukemia virus / Q000235:genetics*; D008980:Moloney murine sarcoma virus / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology / Q000633:toxicity; D017354:Point Mutation; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis*; D012091:Repetitive Sequences, Nucleic Acid; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011993:Recombinant Fusion Proteins; D017239:Paclitaxel