Rapid emergence of methotrexate resistance in cultured mouse cells - PubMed (original) (raw)
- PMID: 6744265
Rapid emergence of methotrexate resistance in cultured mouse cells
H Rath et al. Cancer Res. 1984 Aug.
Abstract
We have examined the time required for mouse 3T6 cells to become resistant to 200 nM methotrexate by three selection protocols: (a) a single-step 0 to 200 nM dose; (b) a two-step 0 to 80 to 200 nM dose; and (c) a multistep 0 to 40 to 80 to 120 to 160 to 200 nM dose. An initial inoculum of 5 X 10(5) cells was grown to 10(6) cells at each increment of methotrexate, reduced to 5 X 10(5) cells, and again grown to 10(6) cells at the next increment. The total elapsed time required for an initial inoculum of 5 X 10(5) cells to grow to 1 X 10(6) cells resistant to 200 nM methotrexate was 45, 21, and 6.5 days, respectively, for the three drug dosage schedules. The single-step resistant variants did not contain amplified dihydrofolate reductase genes, whereas cells resistant to 200 nM methotrexate by the two stepwise selections were resistant as a result of a 6-fold amplification of the dihydrofolate reductase gene. We conclude that the resistance to 200 nM methotrexate resulting from gene amplification did not preexist in the initial population but was generated during the selection process. These results are discussed in terms of the emergence of drug resistance during the course of chemotherapy of tumors.
Similar articles
- Gene amplification and drug resistance in mammalian cells.
Schimke RT, Brown PC, Kaufman RJ. Schimke RT, et al. Natl Cancer Inst Monogr. 1982;60:79-86. Natl Cancer Inst Monogr. 1982. PMID: 7121575 - Stimulation of methotrexate resistance and dihydrofolate reductase gene amplification by c-myc.
Denis N, Kitzis A, Kruh J, Dautry F, Corcos D. Denis N, et al. Oncogene. 1991 Aug;6(8):1453-7. Oncogene. 1991. PMID: 1886715 - Acquisition and loss of amplified genes: dramatic effects of hormones, tumor promoters and cytotoxic drugs.
Varshavsky A, Barsoum J, Roninson I, Snapka R. Varshavsky A, et al. Princess Takamatsu Symp. 1983;14:235-54. Princess Takamatsu Symp. 1983. PMID: 6394591 Review. - Gene amplification and altered enzymes as mechanisms for the development of drug resistance.
Bertino JR, Carman MD, Weiner HL, Cashmore A, Moroson BA, Srimatkandada S, Schornagel JH, Medina WD, Dube SK. Bertino JR, et al. Cancer Treat Rep. 1983 Oct;67(10):901-4. Cancer Treat Rep. 1983. PMID: 6354438 Review.
Cited by
- Mathematical models of gene amplification with applications to cellular drug resistance and tumorigenicity.
Kimmel M, Axelrod DE. Kimmel M, et al. Genetics. 1990 Jul;125(3):633-44. doi: 10.1093/genetics/125.3.633. Genetics. 1990. PMID: 2379824 Free PMC article. - Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells.
Young SD, Marshall RS, Hill RP. Young SD, et al. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9533-7. doi: 10.1073/pnas.85.24.9533. Proc Natl Acad Sci U S A. 1988. PMID: 3200838 Free PMC article. - Conceptualizing a tool to optimize therapy based on dynamic heterogeneity.
Liao D, Estévez-Salmerón L, Tlsty TD. Liao D, et al. Phys Biol. 2012 Dec;9(6):065005. doi: 10.1088/1478-3975/9/6/065005. Epub 2012 Nov 29. Phys Biol. 2012. PMID: 23197078 Free PMC article. - Generalized principles of stochasticity can be used to control dynamic heterogeneity.
Liao D, Estévez-Salmerón L, Tlsty TD. Liao D, et al. Phys Biol. 2012 Dec;9(6):065006. doi: 10.1088/1478-3975/9/6/065006. Epub 2012 Nov 29. Phys Biol. 2012. PMID: 23197162 Free PMC article. - Toxicity of folic acid analogs in cultured human cells: a microtiter assay for the analysis of drug competition.
Roos DS, Schimke RT. Roos DS, et al. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4860-4. doi: 10.1073/pnas.84.14.4860. Proc Natl Acad Sci U S A. 1987. PMID: 3496598 Free PMC article.