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PubMed1981

The acute effects of furosemide, ethacrynic acid and chlorothiazide on the renal tubular handling of uric acid in the chicken.

Birds resemble man in that both lack uricase and therefore uric acid (urate) is the end product of purine metabolism in both animals. Although urate is largely excreted by the kidneys in both species, it has generally been accepted that the renal handling of urate in the chicken differs from that in man in that drugs which are known to be uricosuric in man do not produce a uricosuric response in birds. This suggests that tubular reabsorption of urate is either minimal or lacking in birds. The present study used the in vivo Sperber chicken technique to investigate the acute effects of diuretics which are known to alter urate clearance in man. Our results show that both ethacrynic acid and furosemide can selectively increase the apparent tubular excretion of [14C]urate, suggesting that the chicken kidney is capable of reabsorbing urate. Chlorothiazide is known to decrease urate clearance in both man and the chicken and was found in this study also to decrease the renal tubular excretion of [14C]urate formed within the chicken kidney during infusion of [14C]hypoxanthine or [14C]guanine.

Animals↗

PubMedDate not supplied

Chemosensitisation of alkylating agents by pentoxifylline, O6-benzylguanine and ethacrynic acid in haematological malignancies.

The effects of resistance modifiers (RM) on the cytotoxicity of mafosfamide (MAF), bis-chloroethylnitrosourea (BCNU) and dacarbazine (DTIC) were evaluated by the MTT colorimetric assay in isolated lymphocytes and blast cells derived from patients with chronic lymphatic leukaemia (CLL; n = 28) and acute myeloid leukaemia (AML; n = 30), or from healthy donors (n = 19). Pentoxifylline (PTX) has been shown to restore sensitivity to alkylating drugs by interfering with DNA repair. PTX (10 microM) significantly sensitised leukaemic blasts to the cytotoxic effect of MAF. In 8 out of 30 AML samples, sensitisation ratios (SRs; i.e. cytotoxic drug ID50s in the presence or absence of RM) for MAF in the presence of PTX were > 2 ranging up to 4.2. Inhibition of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) by O6-benzylguanine (O6-BG; 50 microM) enhanced the cytotoxicity of DTIC in CLL lymphocytes. SRs > 2 for DTIC in the presence of O6-BG were observed in 7 out of 28 CLL specimens. Sensitisation was generally greater in the more chemo-resistant specimens. Ethacrynic acid (EA; 1 microM), an inhibitor of glutathione-S-transferases (GST), failed to influence the cytotoxicity of alkylating agents in any cell type. Also, all examined RMs did not sensitive leukaemic cells to the cytotoxic effect of BCNU. The data show significant chemosensitisation of leukaemic cells to alkylating agents by PTX and O6-BG, indicating a potential clinical use of these substances as RM in patients.

Acute Disease↗

PubMed1992

Effect of buthionine sulfoximine and ethacrynic acid on cytotoxic activity of mitomycin C analogues BMY 25282 and BMY 25067.

BMY 25282 and BMY 25067, analogues of mitomycin C (MMC), were synthesized in an attempt to increase the therapeutic potential of the parent drug. The present studies were undertaken to determine if the cytotoxicity of MMC or its analogues is affected by cellular glutathione (GSH) and/or GSH transferase (GST) levels by using sensitive (P388/S) and multidrug resistant (P388/R-84) mouse leukemia cells as a model. P388/R-84 cells were cross-resistant to all three drugs. BMY 25067 was > 100 times more cytotoxic than MMC in both the cells. MMC and BMY 25282 produced significantly lower DNA interstrand cross-links (ISC) in P388/R-84 cells, whereas BMY 25067 induced ISC formation was comparable in these cells. GSH depletion with D,L-buthionine-S,R-sulfoximine (BSO) increased sensitivity to MMC, BMY 25282, and BMY 25067 by 3.4-, 4.1-, and 1.8-fold, respectively, in the resistant cells. Pretreatment of P388/R-84 cells with a nontoxic concentration of ethacrynic acid (EA) (10 micrograms/ml for 1 h), an inhibitor of GST activity, also resulted in a significant increase in the cytotoxic activities of MMC and BMY 25282 (3.8- and 3.1-fold, respectively), but not of BMY 25067. Combined pretreatment of P388/R-84 cells with BSO and EA caused further increase in the cytotoxic activities of both MMC and BMY 25282. Potentiation of BMY 25067 cytotoxicity by combined BSO and EA pretreatments was similar to that observed by BSO pretreatment alone. The ISC formation by MMC and BMY 25282 were also increased significantly by BSO or EA pretreatment in these cells. Whereas BSO treatment increased BMY 25067 induced ISC formation, it was not affected by EA pretreatment. These results suggest that (a) a potentiation of the cytotoxic activity of MMC or BMY 25282 can be achieved by GSH depletion and/or GST inhibition, (b) the enhanced cytotoxicity may be caused at least in part by the increased formation of drug-DNA cross-links, and (c) the mechanism of BMY 25067 cytotoxicity may be different from the other two drugs. The results of the present study also suggest that BMY 25067 may be seriously considered for further clinical development because it is much more active than MMC, and unlike the parent drug cytotoxicity of BMY 25067 does not seem to be affected by GST levels, which have been suggested to play an important role in cellular resistance to several cancer chemotherapy drugs.

Animals↗

PubMed1966