Aldehyde-dehydrogenase gene-transduced hematopoietic cell line K562 overcomes the cytoxicity of cyclophosphamide in vitro.
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 cells lines in vitro, this study tested whether ALDH1 overexpression could directly induce cyclophosphamide resistance. Results showed that a retroviral vector was used to transduce full-length human ALDH1 cDNA into human hematopoietic cell line K562 that was then tested for resistance to 4-hydroxycyclophosphamide (4-HC), an active analogue of cyclophosphamide. Overexpression of the ALDH1 gene resulted in a significant increases in cyclophosphamide resistance in transduced K562 cells (50% inhibition concentration, IC50 = 10 micro mol/L). These findings indicate that ALDH1 overexpression is sufficient to induce cyclophosphamide resistance in vitro and provide a basis for testing the efficacy of ALDH1 gene transduction to protect bone marrow cells from high-dose cyclophosphamide in vivo.
Yang
Xiao-Wei
XW
Jiangsu Institue of Hematology, The First Affiliated Hospital of Suzhou University, Suzhou 215006, China.
Wang
Wei
W
Fu
Jian-Xin
JX
Cen
Jian-Nong
JN
Guo
Feng
F
Xia
Xue-Ming
XM
Chen
Zi-Xing
ZX
D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
D018906:Antineoplastic Agents, Alkylating; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D000444:Aldehyde Dehydrogenase