Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer

Michele Magni, Suzy Shammah, Raffaella Schiró, Wilfredo Mellado, Riccardo Dalla-Favera, A. Massimo Gianni

Research output: Contribution to journalArticle

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Abstract

The identification of genes inducing resistance to anticancer chemotherapeutic agents and their introduction into hematopoietic cells represents a promising approach to overcome bone marrow toxicity, the limiting factor for most high-dose chemotherapy regimens. Because resistance to cyclophosphamide has been correlated with increased levels of expression of the aldehyde-dehydrogenase (ALDH1) gene in tumor cell lines in vitro, we tested whether ALDH1 overexpression could directly induce cyclophosphamide resistance. We have cloned a full-length human ALDH1 cDNA and used retroviral vectors to transduce it into human (U937) and murine (L1210) hematopoietic cell lines that were then tested for resistance to maphosphamide, an active analogue of cyclophosphamide. Overexpression of the ALDH1 gene resulted in a significant increases in cyclophosphamide resistance in transduced L1210 and U937 cells (50% inhibition concentration [IC50], ≃13μmol/L). The resistant phenotype was specifically caused by ALDH1 overexpression as shown by its reversion by disulfiram, a specific ALDH1 inhibitor. ALDH1 transduction into peripheral blood human hematopoietic progenitor cells also led to significant increases (4- to 10-fold; IC50, ≃3 to 4 μmol/L) in cyclophosphamide resistance in an in vitro colony-forming assay. These findings indicate that ALDH1 overexpression is sufficient to induce cyclophosphamide resistance in vitro and provide e basis for testing the efficacy of ALDH1 gene transduction to protect bone marrow cells from high- dose cyclophosphamide in vivo.

Original languageEnglish
Pages (from-to)1097-1103
Number of pages7
JournalBlood
Volume87
Issue number3
Publication statusPublished - Feb 1 1996

Fingerprint

Gene transfer
Aldehyde Dehydrogenase
Cyclophosphamide
Genes
Cells
Inhibitory Concentration 50
Bone
Disulfiram
aldehyde dehydrogenase 1
U937 Cells
Chemotherapy
Hematopoietic Stem Cells
Tumor Cell Line
Bone Marrow Cells
Antineoplastic Agents
Toxicity
Tumors
Assays
Blood
Complementary DNA

ASJC Scopus subject areas

  • Hematology

Cite this

Magni, M., Shammah, S., Schiró, R., Mellado, W., Dalla-Favera, R., & Gianni, A. M. (1996). Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood, 87(3), 1097-1103.

Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. / Magni, Michele; Shammah, Suzy; Schiró, Raffaella; Mellado, Wilfredo; Dalla-Favera, Riccardo; Gianni, A. Massimo.

In: Blood, Vol. 87, No. 3, 01.02.1996, p. 1097-1103.

Research output: Contribution to journalArticle

Magni, M, Shammah, S, Schiró, R, Mellado, W, Dalla-Favera, R & Gianni, AM 1996, 'Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer', Blood, vol. 87, no. 3, pp. 1097-1103.
Magni M, Shammah S, Schiró R, Mellado W, Dalla-Favera R, Gianni AM. Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood. 1996 Feb 1;87(3):1097-1103.
Magni, Michele ; Shammah, Suzy ; Schiró, Raffaella ; Mellado, Wilfredo ; Dalla-Favera, Riccardo ; Gianni, A. Massimo. / Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. In: Blood. 1996 ; Vol. 87, No. 3. pp. 1097-1103.
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