TY - JOUR
T1 - Changes in Glutathione Content and Resistance to Anticancer Agents in Human Stomach Cancer Cells Induced by Treatments with Melphalan in Vitro
AU - Barranco, S. C.
AU - Weintraub, B.
AU - Beasley, E. G.
AU - MacLean, K. K.
AU - Shaeffer, J.
AU - Liu, N. H.
AU - Schellenberg, K.
AU - Townsend, C. M.
PY - 1990/6/15
Y1 - 1990/6/15
N2 - 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 jig/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, l-(2-chloroethyl)-3-(4-methylcyclo-hexyl)-l-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 56 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.
AB - 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 jig/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, l-(2-chloroethyl)-3-(4-methylcyclo-hexyl)-l-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 56 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.
UR - http://www.scopus.com/inward/record.url?scp=0025299329&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0025299329&partnerID=8YFLogxK
M3 - Article
C2 - 2340510
AN - SCOPUS:0025299329
SN - 0008-5472
VL - 50
SP - 3614
EP - 3618
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -