Msh2 deficiency attenuates but does not abolish thiopurine hematopoietic toxicity in msh2-/- mice.
The amount of MSH2 protein, a major component of the mismatch repair system, was found to differ >10-fold in leukemia cells from children with newly diagnosed acute lymphoblastic leukemia, with a subgroup of patients (17%) having undetectable MSH2 protein. We therefore used a murine Msh2 knockout model to elucidate the in vivo importance of MSH2 protein expression in determining thiopurine hematopoietic cytotoxicity. After mercaptopurine (MP) treatment (30 mg/kg/day for 14 days), there was a significantly greater decrease in circulating leukocytes in Msh2+/+ and Msh2+/- mice when compared with Msh2-/- mice (p < 0.002). Likewise, the decrease in erythrocyte counts was more prominent in mice with at least one functional Msh2 allele. MP doses of more than 50 mg/kg/day for 14 days resulted in treatment-related deaths, but Msh2-/- mice had a significant survival advantage (p = 0.02). Murine embryonic fibroblasts (MEFs) from Msh2+/+ mice also exhibited increased sensitivity to MP when compared with MEFs from Msh2-/- mice (IC50, 3.8 +/- 0.1 microM versus 11.9 +/- 1.3 microM, p < 0.001). After MP treatment, deoxythioguanosine incorporation into DNA was similar in mice and MEFs with each of the Msh2 genotypes. Electromobility shift assay experiments identified an Msh2-containing GT- or GST-DNA-nuclear protein complex in Msh2+/+ but not Msh2-/- MEFs. Together, these findings establish that hematopoietic toxicity in vivo after treatment with mercaptopurine is attenuated but not abolished by MSH2 deficiency.
Krynetskaia
Natalia F
NF
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Brenner
Timothy L
TL
Krynetski
Eugene Y
EY
Du
Weinan
W
Panetta
John C
JC
Ching-Hon
Pui
P
Evans
William E
WE
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013866:Thioguanine / Q000378:metabolism / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D004247:DNA; D015122:Mercaptopurine; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D013866:Thioguanine