Event-by-event analysis of collision-induced cluster-ion fragmentation: sequential monomer evaporation versus fission reactions.

The most abundant decay channels have been studied quantitatively for high-energy (60 keV/amu) cluster ions H (3) (+)(H (2))(m = 1-14) colliding with He atoms employing a recently developed multicoincidence technique for the simultaneous detection of the correlated fragments on an event-by-event basis. This allows us to identify decay reactions and their underlying decay mechanisms responsible for the occurrence of the U-shaped fragmentation pattern.

Inhibition of lung tumorigenesis by NSAIDS: a working hypothesis.

A 7-week treatment with the tobacco carcinogen NNK induced 8-10 lung adenomas per A/J mouse. NNK suppressed humoral and cellular immune responses and increased plasma PGE2 and LTB4 levels. This protocol is particularly suitable for testing NSAIDs and lipoxygenase inhibitors as cancer preventive agents. Sulindac and ASA inhibited lung tumorigenesis by 52 and 60%, respectively, attenuated the suppressive effect of NNK, and lowered the plasma PGE2 to basal levels. In contrast, naproxen neither inhibited lung tumorigenesis nor increased NNK-suppressed NK cell cytotoxicity. NSAIDs and lipoxygenase inhibitors had additive preventive efficacies against NNK-induced lung tumorigenesis. However, sulindac was not effective in preventing lung tumorigenesis induced by B[a]P, which lacks immunosuppressive activity. These results and those published by other investigators lead to the following hypothesis: Reactive intermediates derived from NNK interfere with the stimulation of the complex NF-kappa B/I kappa B. NF-kappa B is involved in the regulation of immune and inflammatory responses. The authors propose that NNK-derived intermediates induce the expression of COX-2 and lipoxygenase involved in NNK activation. This hypothesis provides a rationale for the lack of efficacy of naproxen to prevent tumorigenesis, to attenuate NNK-induced synthesis of PGE2, and to increase NK cell cytotoxicity. According to this hypothesis, PGE2 synthesis and induction of apoptosis contribute to varying degrees to the mechanism of cancer prevention.

Antitumorigenic and antipromoting activities of ellagic acid, ellagitannins and oligomeric anthocyanin and procyanidin.

We previously showed that ellagic acid (EA) was inhibiting lung tumorigenesis induced by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. In the present study, we observed that the inhibition of lung tumorigenesis was independent of the solvent used to purified EA. Pomegranate peels extract containing punicalagin (alpha and beta anomers) (10 g/kg diet) and oligomeric anthocyanins (6 g/kg diet) did not inhibit lung tumorigenesis. Raspberry extract (2x15 mg) containing sanguiin H6 and lambertianin D as well as oligomeric procyanidins (2x15 mg) inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity by about 30%. The same treatments inhibit TPA-stimulated hydroperoxide (HPx) production by about 30 and 70%. Raspberry ellagitannins and oligomeric procyanidins respectively inhibit TPA stimulated DNA synthesis by 42 and 26%. Our results su est that hydrolyzable and condensed tannins from various sources, which can inhibit the ODC, HPx, and DNA responses to TPA, might also inhibit the tumor-promoting activity of this agent. The results of this study show that EA and ellagitannins have different antitumorigenic and antipromoting activities.

Effects of NSAIDs on NNK-induced pulmonary and gastric tumorigenesis in A/J mice.

Non-steroidal anti-inflammatory drugs (NS-AIDs) are among the most widely prescribed drugs. In this study, we compared the efficacies of four NSAIDs to inhibit lung tumorigenesis in A/J mice. The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was given in drinking water between week 0 and week +7. Groups of 25 mice were fed sulindac (123 mg/kg diet), ibuprofen (263 mg/kg), piroxicam (25 mg/kg) or naproxen (230 mg/kg) in AIN-76A diet from week -2 to the end of the bioassay (week +23). Sulindac was the most effective inhibitor and reduced lung tumor multiplicity by 51%. Ibuprofen and piroxicam reduced lung multiplicity by 38% and 30%, respectively. Naproxen demonstrated no inhibitory capacity. Forestomach tumor multiplicity and incidence were both reduced by sulindac and ibuprofen. Sulindac administered from week -2 to week +7 was less effective (28% inhibition) than when given throughout the bioassay. Sulindac induced more intestinal adhesions than any other NSAID and was directly related to the cumulative dose of sulindac. These results show that chemoprevention of lung tumorigenesis by NSAIDs is not limited to sulindac although it is the most effective.

Biodistribution of ellagic acid and dose-related inhibition of lung tumorigenesis in A/J mice.

Ellagic acid (EA), derived from fruit ellagitannins, is known to be antimutagenic and anticarcinogenic in various animal tumor models. In this study, EA at a dose of 4 g/kg diet inhibited multiplicity of tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice by 54%. This inhibition was dose related between 0.06 and 4.0 g/kg diet. In contrast, two related compounds, esculin and esculetin, had no effect on lung tumorigenesis. The biodistribution of EA was studied as a function of dose and time after gavage of EA. The levels of EA in the lung were directly proportional to the dose of EA between 0.2 and 2.0 mmol. The maximum level of EA, corresponding to 21.3 nmol/g, was observed 30 minutes after gavage with 2.0 mmol of EA/kg body wt, which corresponds to only 70 ppm of the administered dose. The levels in liver tissues were 10-fold lower and reached a maximum 30 minutes after gavage. At this interval, the blood level of EA was 1 nmol/ml. The inclusion of EA in cyclodextrin doubles the level of EA in lung tissues. These results demonstrate that EA localizes preferentially in lung tissues and confirm that EA administered orally can inhibit lung tumorigenesis.