Dietary freeze-dried black raspberries (BRBs) inhibit N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the Fischer 344 rat esophagus. To determine the mechanistic basis of the anti-initiating effects of BRBs, NMBA metabolism was studied in esophageal explant cultures and in liver microsomes taken from rats fed with AIN-76A diet or AIN-76A diet containing 5% or 10% BRBs. Five percent and 10% dietary BRBs inhibited NMBA metabolism in explants (26% and20%) and in microsomes (22% and28%), but the inhibition was not dose dependent. To identify active inhibitory component(s) in BRBs, esophageal explants and liver microsomes from control rats were treated in vitro with an ethanol extract of BRBs or with individual components of BRBs [ellagic acid (EA) and two anthocyanins (cyanidin-3-glucoside and cyanidin-3-rutinoside)]. NMBA metabolism in explants was inhibited maximally by cyanidin-3-rutinoside (47%) followed by EA (33%), cyanidin-3-glucoside (23%),and the extract (11%). Similarly, in liver microsomes, the inhibition was maximal by cyanidin-3-rutinoside (47%) followed by EA (33%) and cyanidin-3-glucoside (32%). Phenylethylisothiocyanate (PEITC), a potent inhibitor of NMBA tumorigenesis in rat esophagus, was a stronger inhibitor of NMBA metabolism in vivo and in vitro than BRBs or their components. Dietary BRBs and PEITC induced glutathione S-transferase activity in the liver.

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Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.

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The JOK-1 hairy cell leukemia derived cell line has been propagated as a subcutaneous tumor in nude mice. After the tumor had been serially transplanted for at least two successive generations, mice were treated with either dimethylsulfoxide or hexamethylene bisacetamide (HMBA). These agents have been shown to induce terminal leukemic cell differentiation in vitro. Our results indicated that these agents had an in vivo growth inhibitory effect, with HMBA exerting a dose-dependent response. Histopathological examination revealed massive areas of necrosis with no overt signs of cellular differentiation. These data suggest that in vitro inducers of differentiation may act via another mechanism in vivo.

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