Cytotoxic effects of glutathione synthesis inhibition by L-buthionine-(SR)-sulfoximine on human and murine tumor cells.
The glutathione (GSH) synthesis inhibitor, buthionine sulfoximine (BSO) was tested for cytotoxicity and thiol depletion in murine and human tumor cells in vitro, and for its antitumor activity and toxicity in vivo. The cell lines used in these studies included murine L-1210 leukemia, human RPMI 8226 myeloma, MCF-7 breast cancer and WiDr colon carcinoma. Soft agar colony forming assays showed that BSO was most effective at reducing tumor colony formation when exposed continuously to cells in vitro. Drug concentrations which inhibited colony formation to 50% of control levels ranged from 2.0-6.2 mM (for 1 hour exposures), 2-100 mM for 24 hour exposures and 0.4-1.40 microM (for continuous BSO exposures). Human myeloma cells proved most sensitive to BSO. In vitro cytotoxicity correlated with depletion of intracellular nonprotein sulfhydryls to less than or equal to 10% of control values in both L-1210 and 8226 cells. This was routinely achieved with prolonged exposures to mM BSO concentrations for greater than 24 hours. Normal mice tolerated high BSO doses (up to 5.0 g/kg) without evidence of acute toxicity. BSO was not active against L-1210 leukemia-bearing DBA/2 mice. When tested in vivo against MOPC-315 plasmacytoma-bearing BALB/c mice, BSO was not active at doses up to 4.0 g/kg. In contrast, the bifunctional alkylating agent melphalan (L-PAM) was active against MOPC-315 and this activity was enhanced by a 24 hour pretreatment of mice with 50 mg/kg of L-BSO.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009369:Neoplasms / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000032:analysis
D000970:Antineoplastic Agents; D013438:Sulfhydryl Compounds; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan