Changes in glutathione content and resistance to anticancer agents in human stomach cancer cells induced by treatments with melphalan in vitro

S. C. Barranco, C. M. Townsend, B. Weintraub, E. G. Beasley, K. K. MacLean, J. Shaeffer, N. H. Liu, Courtney Townsend

Research output: Contribution to journalArticle

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Abstract

A clone of a human gastric carcinoma cell line was used to determine whether cells which had survived a treatment with Melphalan would express altered survival responses when treated again with this agent 1 week or more later. Cells were treated for 1 h each week with 2 ng/ml (99% lethal dose). After the first Melphalan treatment, the cells exhibited a 10-fold reduction in sensitivity to Melphalan. This was preceded by a 2-fold increase in intracellular glutathione content. By the end of 10 weekly treatments, the cells were 50 times more resistant than controls (based on changes in survival fractions). They also demonstrated collateral resistance to Actinomycin D, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, galactitol, and X-rays, but showed no change in sensitivity to 5-fluorouracil, bleomycin, and Adriamycin. The resistance to Melphalan was not reversible when treatment was withheld for 4 weeks on two different occasions. The results suggest that treatment with a high dose of Melphalan either selects an existing population of cells with a high GSH content or induces mutations leading to increased GSH content or both, and this results in the expression of greater Melphalan resistance at the time of other treatments. Furthermore, Melphalan treatment stimulates a 50% increase in GSH content in resistant cells in just 6 h, an 85% increase in 36 h, and a 150% increase in 72 h. L-Buthionine sulfoximine partially reversed the expression of resistance to Melphalan by inducing a 60% reduction in intracellular glutathione content.

Original languageEnglish (US)
Pages (from-to)3614-3618
Number of pages5
JournalCancer Research
Volume50
Issue number12
StatePublished - Jun 15 1990

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Melphalan
Antineoplastic Agents
Stomach Neoplasms
Glutathione
Galactitol
Buthionine Sulfoximine
Survival
In Vitro Techniques
Bleomycin
Fluorouracil
Doxorubicin
Stomach
Clone Cells
X-Rays
Carcinoma
Cell Line
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Barranco, S. C., Townsend, C. M., Weintraub, B., Beasley, E. G., MacLean, K. K., Shaeffer, J., ... Townsend, C. (1990). Changes in glutathione content and resistance to anticancer agents in human stomach cancer cells induced by treatments with melphalan in vitro. Cancer Research, 50(12), 3614-3618.

Changes in glutathione content and resistance to anticancer agents in human stomach cancer cells induced by treatments with melphalan in vitro. / Barranco, S. C.; Townsend, C. M.; Weintraub, B.; Beasley, E. G.; MacLean, K. K.; Shaeffer, J.; Liu, N. H.; Townsend, Courtney.

In: Cancer Research, Vol. 50, No. 12, 15.06.1990, p. 3614-3618.

Research output: Contribution to journalArticle

Barranco, SC, Townsend, CM, Weintraub, B, Beasley, EG, MacLean, KK, Shaeffer, J, Liu, NH & Townsend, C 1990, 'Changes in glutathione content and resistance to anticancer agents in human stomach cancer cells induced by treatments with melphalan in vitro', Cancer Research, vol. 50, no. 12, pp. 3614-3618.
Barranco SC, Townsend CM, Weintraub B, Beasley EG, MacLean KK, Shaeffer J et al. Changes in glutathione content and resistance to anticancer agents in human stomach cancer cells induced by treatments with melphalan in vitro. Cancer Research. 1990 Jun 15;50(12):3614-3618.
Barranco, S. C. ; Townsend, C. M. ; Weintraub, B. ; Beasley, E. G. ; MacLean, K. K. ; Shaeffer, J. ; Liu, N. H. ; Townsend, Courtney. / Changes in glutathione content and resistance to anticancer agents in human stomach cancer cells induced by treatments with melphalan in vitro. In: Cancer Research. 1990 ; Vol. 50, No. 12. pp. 3614-3618.
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abstract = "A clone of a human gastric carcinoma cell line was used to determine whether cells which had survived a treatment with Melphalan would express altered survival responses when treated again with this agent 1 week or more later. Cells were treated for 1 h each week with 2 ng/ml (99{\%} lethal dose). After the first Melphalan treatment, the cells exhibited a 10-fold reduction in sensitivity to Melphalan. This was preceded by a 2-fold increase in intracellular glutathione content. By the end of 10 weekly treatments, the cells were 50 times more resistant than controls (based on changes in survival fractions). They also demonstrated collateral resistance to Actinomycin D, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, galactitol, and X-rays, but showed no change in sensitivity to 5-fluorouracil, bleomycin, and Adriamycin. The resistance to Melphalan was not reversible when treatment was withheld for 4 weeks on two different occasions. The results suggest that treatment with a high dose of Melphalan either selects an existing population of cells with a high GSH content or induces mutations leading to increased GSH content or both, and this results in the expression of greater Melphalan resistance at the time of other treatments. Furthermore, Melphalan treatment stimulates a 50{\%} increase in GSH content in resistant cells in just 6 h, an 85{\%} increase in 36 h, and a 150{\%} increase in 72 h. L-Buthionine sulfoximine partially reversed the expression of resistance to Melphalan by inducing a 60{\%} reduction in intracellular glutathione content.",
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