Relationship between glutathione levels and drug or radiation sensitivities in human gastric cancer cell lines in vitro.

Permanent cell lines and clones established from an untreated patient (AGS cells) with gastric carcinoma, and from a similar patient who had been treated with Adriamycin, 5FU and cytoxan (SII cells) were used in a study that compared their drug and radiation survival sensitivities to their glutathidine (GSH) values. The SII parental cell line was more resistant than the AGS cells in vitro to chlorambucil, ACT D, Adria, Bleo, and X-rays. This greater resistance was positively correlated with GSH values that were 1.77 times higher than in the AGS parental cell line. By contrast the SII parental cells were more sensitive than the AGS cells to MeCCNU and Melphalan. The drug and radiation sensitivities expressed among the clones of the two cell lines were heterogeneous and did not correlate with their GSH values.

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

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 micrograms/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.