ascorbic-acid and Neoplasms--Squamous-Cell

Our previous data showed that F344/DuCrj and LEW/Crj rat strains bearing the type a catalase-1 locus (CS1a) are sensitive to the promoting activity of sodium L-ascorbate (Na-AsA) in 2-stage urinary bladder carcinogenesis, whereas ODS/Shi and WS/ Shi rat strains bearing the type b catalase-1 locus (CS1b) are resistant. In present study, we investigated the susceptibility of F344/Shi rats also bearing the CS1 to the Na-AsA-promoting effects on bladder tumor development. Male rats, 6 weeks old, were given 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for 4 weeks, then fed either basal diet supplemented with 5% Na-AsA or no chemicals for 32 weeks. The rats given BBN alone had a few small carcinomas in the urinary bladder. In contrast, animals administered BBN-Na-AsA had many large carcinomas. Administration of Na-AsA was associated with significant elevation of urinary pH and L-ascorbic acid. The results indicate that F344/Shi rats are sensitive to the promoting effects of Na-AsA on 2-stage urinary bladder carcinogenesis, and thus that the CS1 locus may not influence susceptibility to promotion.

Topics: Alleles; Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma, Transitional Cell; Catalase; Disease Susceptibility; Hyperplasia; Male; Neoplasms, Squamous Cell; Papilloma; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

Photofrin, a photosensitizer used in the photodynamic therapy of cancer, selectively localizes in cellular membranes. Upon exposure to visible light, Photofrin produces singlet oxygen (1O2), which reacts with membrane polyunsaturated fatty acids forming lipid hydroperoxides. Transition metals, such as Fe2+, catalyze the production of cytotoxic free radicals from lipid hydroperoxides. Ascorbate reduces ferric to ferrous iron, further augmenting lipid peroxidation. Therefore, to increase the efficacy of Photofrin photosensitization, we added 20 microM ferrous sulfate and 100 microM ascorbic acid, in an aqueous layer over SCC-25 oral squamous cell carcinoma cells during in vitro illumination. In electron paramagnetic resonance spin trapping experiments, using POBN (alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone), we observed that the presence of this pro-oxidant combination greatly increases the production of membrane-derived lipid free radicals. The effect was time dependent but only partially concentration dependent. Trypan blue dye exclusion demonstrated that this increase in lipid radical formation correlated with cytotoxicity. These observations support the hypothesis that Photofrin photosensitization leads to lipid hydroperoxide formation, which increases the cell's susceptibility to iron-induced Fenton chemistry. The resulting free radical-mediated lipid peroxidation results in cell death. From these data we hypothesize that the efficacy of photodynamic therapy of superficial cancer might be increased by the topical application of the pro-oxidant combination of iron and ascorbate. Furthermore, their use will probably allow lower doses of Photofrin without compromising antitumor effect.

Topics: Antineoplastic Agents; Ascorbic Acid; Dihematoporphyrin Ether; Drug Interactions; Ferrous Compounds; Free Radicals; Humans; Mouth Neoplasms; Neoplasms, Squamous Cell; Photosensitizing Agents; Tumor Cells, Cultured