diethyl-maleate and Stomach-Neoplasms

The modifying effect of diethyl maleate (DEM) on gastric tumor development was studied in rats initially given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and hypertonic sodium chloride (H-NaCl 10% or 5%). Groups of animals were maintained with or without a 0.2% DEM dietary supplement after treatment with MNNG and H-NaCl and sacrificed at week 20. Forestomachs and livers cytosolic NAD(P)H:quinone-acceptor oxidoreductase (QR) activity was also analyzed. The incidences of forestomach severe hyperplasias in the MNNG + H-NaCl --> DEM groups were also significantly higher than in the MNNG + H-NaCl alone group (P < 0.01 and P < 0.05 for 5% and 10% groups, respectively). Similarly, in the glandular stomach, the numbers of preneoplastic pepsinogen 1 altered pyloric glands (PAPGs) in the MNNG + H-NaCl --> DEM groups were significantly increased (P < 0.01 for both concentrations). The QR activities in the groups treated with DEM showed 2- to 3-fold increases as compared with the control level. The results indicate that treatment with 0.2% DEM after MNNG initiation exerts enhancing effects on both forestomach and glandular stomach carcinogenesis. Induction of QR, a Phase II enzyme, activity in the rat stomach by DEM may be associated with promotion of stomach carcinogenesis rather than inhibition.

Topics: Animals; Body Weight; Carcinogenicity Tests; Carcinogens; Carcinoma, Squamous Cell; Gastric Mucosa; Male; Maleates; Methylnitronitrosoguanidine; NAD(P)H Dehydrogenase (Quinone); Papilloma; Pepsinogen A; Rats; Rats, Wistar; Saline Solution, Hypertonic; Stomach; Stomach Neoplasms

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Benzodioxoles; Butylated Hydroxyanisole; Caffeic Acids; Carcinogens; Carcinoma; Catechols; Cell Division; Hydroquinones; Kidney Neoplasms; Male; Maleates; Methylnitronitrosoguanidine; Organ Specificity; Papilloma; Phenols; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms

The long-term effects of butylated hydroxyanisole (BHA), in combination with various other chemicals on the development of forestomach lesions in rats were investigated. BHA is a synthetic antioxidant, and the other agents included the glutathione-depleting agent diethylmaleate (DEM), the anti-inflammatory drugs indomethacin (IM), dexamethazone (DEX), 6-aminocaproic acetate (6-ACA) and FOY (gabexate mesilate), and the vitamin all-trans-retinol acetate (RA). Concurrent treatment with BHA (1% in diet) and DEM, IM, DEX or FOY for 52 weeks inhibited development of forestomach epithelial hyperplasia as compared to BHA alone, while simultaneous treatment with RA enhanced hyperplastic development. However, the inhibition by DEX or FOY was only partial and in the DEX case, in particular, might have been due to weight loss. Since the most effective inhibitory influence on BHA-induced forestomach lesions exerted in this 1-year experiment was by DEM, a further 2-year experiment was conducted to confirm whether DEM actually can exert inhibitory effects on BHA (2% in diet)-induced forestomach carcinogenesis. The results demonstrated that induction of forestomach hyperplasias and papillomas by BHA was significantly reduced by combination treatment with DEM. Both multiplicity and incidence of forestomach papillomas were significantly decreased, while squamous cell carcinoma development showed a tendency for decrease only.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Butylated Hydroxyanisole; Dexamethasone; Drug Antagonism; Hyperplasia; Male; Maleates; Papilloma; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms; Tretinoin

The effects of diethylmaleate (DEM), previously demonstrated to inhibit butylated hydroxyanisole (BHA)-induced forestomach hyperplasia, on BHA promotion of forestomach carcinogenesis in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were examined. Groups of male 6-week-old F344 animals were given a single i.g. administration of 150 mg/kg body weight MNNG and starting 1 week later administered powdered diet containing 1% BHA plus 0.2% DEM, 1% BHA, 0.2% DEM or basal diet alone for 51 weeks. Further groups of rats were treated with 1% BHA plus 0.2% DEM, 1% BHA, 0.2% DEM or basal diet alone without MNNG pretreatment. Histopathological assessment of lesions at week 52 revealed enhancement of MNNG-initiated papilloma (100 versus 50%) and squamous cell carcinoma (100 versus 0%) development by BHA as compared to controls. Additional treatment with DEM, however, significantly reduced the relative incidences of carcinoma in situ (0 versus 35.7%) and squamous cell carcinoma (35.7 versus 100%), as well as BHA-induced forestomach hyperplasia with or without prior MNNG treatment. The results thus clearly demonstrate that DEM acts as a potent antagonist to BHA-promotion of rat forestomach carcinogenesis.

Topics: Animals; Butylated Hydroxyanisole; Cocarcinogenesis; Male; Maleates; Methylnitronitrosoguanidine; Rats; Rats, Inbred F344; Stomach Neoplasms