Zinc-induced reduction in melphalan cytotoxicity: heterogeneity of response of cloned human tumor cells.

Previous studies with cultured human normal fibroblasts indicated that pretreatment of the cells with zinc for 12 h prior to exposure to the alkylating agent melphalan increased survival by seven- to ninefold over survival values obtained in cultures treated with drug only. Comparable pretreatment of cells derived from a variety of human tumors resulted in an increase in survival of 1.7-fold or less. To determine whether the limited responsiveness to zinc represented a general property of tumor cells (which would be characterized by a lack of highly zinc-responsive subpopulations contained within the parental tumor populations), a series of clones was prepared from the A101D human melanoma line and the A549 human alveolar cell carcinoma line. Cells from each clone were then challenged with melphalan with and without zinc pretreatment. Twenty-five percent of the tumor clones exhibited increased resistance to melphalan following pretreatment with zinc (range of 2.1- to 5.2-fold increase in survival), indicating that the parental tumor lines were highly heterogenous in regard to inducibility to a state of reduced sensitivity to melphalan. There was no evidence of a relationship between zinc-induced reductions in toxicity and induced elevations in total intracellular glutathione content, indicating that the primary effect of zinc is not directed toward elevating intracellular levels of glutathione.