TY - JOUR
T1 - Loss of tumorigenicity in a methotrexate-resistant human leukemia cell line
AU - Hill, Anna B.
AU - Trent, Jeffrey M.
AU - Thompson, Floyd H.
AU - Danks, Mary K.
AU - Beck, William T.
N1 - Funding Information:
We thank Margaret Cirtain, Sharon Olson, and Dina Millikin for their excellent technical help, Randy Summers for preparing figures, and Ann Morris for critically reading the manuscript. We thank Dr. Raymond Blakley for help with the HPLC analyses of \[3H\]MTXT. his research was supported by the Leukemia Society of America (A.B.H., Special Fellow; J.M.T., Scholar), a grant from the Del Webb Foundation, and research grants CA40570 and CA30103 (to W.T.B.) from the National Cancer Institute Bethesda, Maryland. This work was also supported in part by Cancer Center Support (CORE) Grants CA21765 (St. Jude Hospital) and CA23074 (University of Arizona) and in part by American Lebanese Syrian Associated Charities.
PY - 1993/10/1
Y1 - 1993/10/1
N2 - We have studied the tumorigenicity of a CCRF-CEM-derived cell line (CEM/MTX-3) resistant to MTX. Eight of nine mice inoculated with drug-sensitive CEM cells developed tumors within 5 weeks, but 16 weeks after inoculation with CEM/MTX-3 cells, none of nine mice developed tumors. We were unable to detect dihydrofolate reductase gene overexpression, amplification, or rearrangement in CEM/MTX-3 cells. Instead, the resistance in CEM/MTX-3 cells appeared to be due largely to decreased methotrexate accumulation. Because tumorigenicity could have been related to intracellular folate levels, we cultured CEM and CEM/MTX-3 cells in folate-rich and folate-deprived media. When inoculated in mice, CEM cells cultured in either medium rapidly formed tumors. As before, CEM/MTX-3 cells grown in either medium did not, suggesting that factors other than low folate levels contributed to the inability of CEM/MTX-3 cells to form tumors. Cytogenetic analysis revealed that the CEM/MTX-3 karyotype contained a unique and complex translocation marker chromosome that was not observed in the CEM cell line and which involved chromosomal breakpoints at bands 11p14, 22p11, and 22p13. Although biochemical mechanisms are not yet delineated, this remodeled chromosome could be related to the loss of tumorigenicity in CEM/MTX-3 cells.
AB - We have studied the tumorigenicity of a CCRF-CEM-derived cell line (CEM/MTX-3) resistant to MTX. Eight of nine mice inoculated with drug-sensitive CEM cells developed tumors within 5 weeks, but 16 weeks after inoculation with CEM/MTX-3 cells, none of nine mice developed tumors. We were unable to detect dihydrofolate reductase gene overexpression, amplification, or rearrangement in CEM/MTX-3 cells. Instead, the resistance in CEM/MTX-3 cells appeared to be due largely to decreased methotrexate accumulation. Because tumorigenicity could have been related to intracellular folate levels, we cultured CEM and CEM/MTX-3 cells in folate-rich and folate-deprived media. When inoculated in mice, CEM cells cultured in either medium rapidly formed tumors. As before, CEM/MTX-3 cells grown in either medium did not, suggesting that factors other than low folate levels contributed to the inability of CEM/MTX-3 cells to form tumors. Cytogenetic analysis revealed that the CEM/MTX-3 karyotype contained a unique and complex translocation marker chromosome that was not observed in the CEM cell line and which involved chromosomal breakpoints at bands 11p14, 22p11, and 22p13. Although biochemical mechanisms are not yet delineated, this remodeled chromosome could be related to the loss of tumorigenicity in CEM/MTX-3 cells.
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U2 - 10.1016/0165-4608(93)90130-E
DO - 10.1016/0165-4608(93)90130-E
M3 - Article
C2 - 8221612
AN - SCOPUS:0027359155
SN - 0165-4608
VL - 70
SP - 48
EP - 55
JO - Cancer Genetics and Cytogenetics
JF - Cancer Genetics and Cytogenetics
IS - 1
ER -