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

G. H. Mickisch, I. Aksentijevich, P. V. Schoenlein, L. J. Goldstein, H. Galski, C. Stahle, D. H. Sachs, I. Pastan, M. M. Gottesman

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1087-1093
Number of pages7
JournalBlood
Volume79
Issue number4
StatePublished - Feb 26 1992

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Chemotherapy
Bone Marrow Transplantation
Transgenic Mice
Bone
Genes
Bone Marrow
Cells
Drug Therapy
Animals
Multiple Drug Resistance
Bone Marrow Cells
Complementary DNA
Daunorubicin
Vinblastine
Dactinomycin
Vincristine
Etoposide
Verapamil
Southern Blotting
Paclitaxel

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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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. / Mickisch, G. H.; Aksentijevich, I.; Schoenlein, P. V.; Goldstein, L. J.; Galski, H.; Stahle, C.; Sachs, D. H.; Pastan, I.; Gottesman, M. M.

In: Blood, Vol. 79, No. 4, 26.02.1992, p. 1087-1093.

Research output: Contribution to journalArticle

Mickisch, GH, Aksentijevich, I, Schoenlein, PV, Goldstein, LJ, Galski, H, Stahle, C, Sachs, DH, Pastan, I & Gottesman, MM 1992, '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', Blood, vol. 79, no. 4, pp. 1087-1093.
Mickisch, G. H. ; Aksentijevich, I. ; Schoenlein, P. V. ; Goldstein, L. J. ; Galski, H. ; Stahle, C. ; Sachs, D. H. ; Pastan, I. ; Gottesman, M. M. / 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. In: Blood. 1992 ; Vol. 79, No. 4. pp. 1087-1093.
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AU - Schoenlein, P. V.

AU - Goldstein, L. J.

AU - Galski, H.

AU - Stahle, C.

AU - Sachs, D. H.

AU - Pastan, I.

AU - Gottesman, M. M.

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N2 - 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.

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