Role of fluroacetate in the toxicity of 2-fluroethylnitrosoureas.
The possible role of fluroacetate in the toxicity and antitumour activity of the fluroethylnitrosoureas, BFNU and FCNU has been studied in CBA mice bearing the TLX5 lymphoma either sensitive (TLXS) or resistant (TLXRT) to nitrosoureas. Treatment of mice bearing either TLXS or TLXRT tumours with either BFNU or FCNU caused an elevation in the citrate levels of heart, kidney and tumour, but not the liver, 24 hr after drug administration. Heart citrate levels were maximally elevated 10-fold, while the levels in kidney and tumour were increased 3- to 6-fold. Tissue levels of flurocitrate were determined by glc after conversion to the ethyl ester. This showed maximum levels of fluroacetate production in heart, with lower levels in kidney, tumour and liver. Treatment of K562 human erythroleukaemia cells in vitro with BFNU caused an inhibition in the production of 14CO2 from 14C palmitate and [U-14C] glucose. These results suggest that some of the effects of the fluroethylnitrosoureas may be related to fluroacetate production and the consequent blocking effect on aconitase. This effect is probably related more to the generalized toxicity of these agents than to their therapeutic efficacy.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002849:Chromatography, Gas / Q000379:methods; D005260:Female; D005463:Fluoroacetates / Q000302:isolation & purification / Q000633:toxicity*; D007668:Kidney / Q000032:analysis; D008099:Liver / Q000032:analysis; D008130:Lomustine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D009206:Myocardium / Q000032:analysis; D009607:Nitrosourea Compounds / Q000627:therapeutic use* / Q000633:toxicity; D014018:Tissue Distribution
D005463:Fluoroacetates; D009607:Nitrosourea Compounds; C015714:bis-(fluoroethyl)nitrosourea; C017318:1-(2-fluoroethyl)-3-cyclohexyl-1-nitrosourea; D008130:Lomustine; C014815:fluoroacetic acid