title: Transplantation of bone marrow cells from transgenic mice expressing the human MDR1 gene results in long-term protection against the myelosuppressive effect of chemotherapy in mice.
abstract: Many human cancers that are initially responsive to chemotherapy eventually fail to respond to treatment. For some drugs, dose escalation that may be required for a cure cannot be achieved because sensitive tissues such as bone marrow (BM) limit cytotoxic therapy. Approaches to prevent or circumvent BM toxicity are therefore a high priority of research on dose escalation protocols. In this study, we have transplanted BM cells from transgenic mice that constitutively express physiologic amounts of a functional human multidrug resistance (MDR1) cDNA to lethally irradiated C57BL/6 x SJL F1 mice (n = 36). From 6 weeks to 10 months after the transplant, all animals contained MDR1 DNA in spleen and BM specimens as indicated by Southern blot analysis, and expressed MDR1 messenger RNA in BM samples as detected by slot blot analysis. In addition, these animals were resistant to the myelosuppressive effect of doxorubicin, daunomycin, taxol, vinblastine, vincristine, etoposide, and actinomycin D, whereas control animals that were reconstituted with normal BM were drug sensitive. Finally, the chemoprotection afforded by the MDR1 gene could readily be reversed by adding chemosensitizers such as cyclosporin A and R-verapamil to chemotherapy. Hence, it appears that BM cells expressing the human MDR1 gene maintain this function after transplantation to host animals for a minimum of 10 months, and confer multidrug resistance to these BM recipients. This selective advantage conferred by expression of the MDR1 cDNA suggests a strategy for the use of MDR1 gene therapy in cancer chemotherapy and for the introduction of otherwise nonselectable genes into BM.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: G H
authors.initials: GH
authors.lastname: Mickisch
authors.forename: I
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: P V
authors.initials: PV
authors.lastname: Schoenlein
authors.forename: L J
authors.initials: LJ
authors.lastname: Goldstein
authors.forename: H
authors.initials: H
authors.lastname: Galski
authors.forename: C
authors.initials: C
authors.lastname: Stahle
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: I
authors.initials: I
authors.lastname: Pastan
authors.forename: M M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015139:Blotting, Southern; D001853:Bone Marrow / Q000737:chemistry / Q000187:drug effects*; D016026:Bone Marrow Transplantation; D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA / Q000032:analysis / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000737:chemistry; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016572:Cyclosporine; D004247:DNA; D014700:Verapamil