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Methotrexate-resistant (MTXR) human breast cancer cells have been obtained which are 1000-fold less sensitive to this drug than the wild type MCF-7 cells from which they were derived. The resistant cells contain approximately a 25-fold increase in the activity of the target enzyme dihydrofolate (DHF) reductase. Enzyme inhibition studies and methotrexate affinity studies fail to reveal any difference in the DHF reductase present in the MTXR cells compared to wild type MCF-7 cells. Cytogenetic analysis demonstrates the presence of elongated marker chromosomes in the resistant cells which are not found in the parental cell line. Analysis of the DNA from MTXR and wild type MCF-7 cells using Southern blot hybridization indicates that the MTXR MCF-7 cells contain more copies of DHF reductase gene sequences than do wild type MCF-7 cells. These experiments also suggest that the amplified DHF reductase gene sequences in MTXR cells may have undergone a uniform structural rearrangement involving the 5' flanking sequences during the process of amplification. MTXR MCF-7 cells respond to estradiol by increasing cell growth, and the level of DHF reductase in the MTXR cells is further induced following administration of estradiol. Radiolabeling studies demonstrate that estrogen stimulates the actual synthesis of DHF reductase in human breast cancer cells.
K H Cowan, and
M E Goldsmith, and
R M Levine, and
S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
December 1981,
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K H Cowan, and
M E Goldsmith, and
R M Levine, and
S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
December 1981,
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K H Cowan, and
M E Goldsmith, and
R M Levine, and
S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
February 2009,
Molecular cancer therapeutics,
K H Cowan, and
M E Goldsmith, and
R M Levine, and
S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
May 1992,
Mutation research,
K H Cowan, and
M E Goldsmith, and
R M Levine, and
S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
March 1982,
Molecular and cellular biology,
K H Cowan, and
M E Goldsmith, and
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S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
August 1985,
Cancer genetics and cytogenetics,
K H Cowan, and
M E Goldsmith, and
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S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
January 1978,
Cold Spring Harbor symposia on quantitative biology,
K H Cowan, and
M E Goldsmith, and
R M Levine, and
S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
March 1982,
Molecular pharmacology,
K H Cowan, and
M E Goldsmith, and
R M Levine, and
S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
January 1979,
Cold Spring Harbor symposia on quantitative biology,
K H Cowan, and
M E Goldsmith, and
R M Levine, and
S C Aitken, and
E Douglass, and
N Clendeninn, and
A W Nienhuis, and
M E Lippman
February 1983,
Biochemistry,
