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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
GH Mickisch, I Aksentijevich, PV Schoenlein, LJ Goldstein, H Galski, C Stahle, DH Sachs, I Pastan and MM Gottesman
Laboratory of Molecular Biology, National Cancer Institute, National
Institutes of Health, Bethesda, MD 20892.
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.
Volume 79,
Issue 4,
pp. 1087-1093,
02/15/1992
Copyright © 1992 by The American Society of Hematology
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