Thesis (Ph. D.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

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Several epidemiological studies .have demonstrated the importance of diet in the development of gastro-intestinal carcinomas in man. This study examines the role of plant phenolics, major components of the human diet. Employing a CHO cell test system, it was observed that phenolics with at least two hydroxyl groups in the ortho position, relative to each other were particularly clastogenic. This activity was abolished by the addition of S9, a rat liver microsomal preparation. The clastogenic activity of these compounds was found to increase with time, alkaline pH, and the presence of transition metals. It was therefore deduced that the source of activity might be an oxidative by-product. High' pressure liquid chromatography was used to separate out these oxidative products. No activity was found to reside in any of the separated components or combinations of components. Further study therefore centred on oxidative products not retained by chromatography and on those labile to this.process. Under oxidative conditions, the presence of hydrogen peroxide was detected. Levels measured were sufficient to explain the clastogenic activity of completely oxidized solutions of phenolic acids. Addition of the enzyme, catalase, appeared to abolish all activity of completely oxidized solutions. Hydrogen peroxide could not, however, account for the genotoxic effects measured in freshly prepared solutions. The presence of superoxide was detected in actively oxidizing solutions of plant phenolics. Its production appeared to be pH-dependent. Addition of superoxide dismutase increased the clastogenic activity of compounds tested, presumably by converting superoxide to peroxide, a more stable oxidative by-product. Addition of tyrosinase, a monophenol oxidase, also increased the clastogenic activity of freshly prepared solutions. Since this enzyme catalyzes the oxidation of several phenolics without subsequent generation of peroxide, it was deduced that phenolic free radicals must also be present which could be at least partially responsible for the enhanced biological activity. Electron spin resonance proved this was the case. Using electron spin resonance, the primary oxidative products were characterized both at high pH and by enzymatic activation. The results obtained agree with those published in the literature. Several reports in the literature have suggested that phenolics may also act as free radical scavengers. The importance of plant phenolics in diet may therefore depend on the oxidative conditions of the system to be tested. Under oxidative conditions, free radicals appear to be generated, which are capable of causing mutations and chromosomal rearrangements. Phenolic oxidation products may therefore play a role as initiators and promotors of carcinogenesis. However, under alternate conditions, phenolics may also act to scavenge free radicals, and could therefore be classed as inhibitors of carcinogenesis. / Science, Faculty of / Zoology, Department of / Graduate

The initiating potential of a range of 4 MeV X-rays was studied using the mouse skin two-stage model of carcinogenesis. A single dose of radiation was followed by promotion with 12-O-tetradecanoyl phorbol-13-acetate (TPA). The effect of TPA on tumor incidence when applied as a single dose 24 hours prior to irradiation was examined. Studies were also designed to investigate the effect of promotion duration on tumor incidence. Animals were promoted with TPA for 10 or 60 weeks. Evidence presented here indicates that ionizing radiation can act as an initiator in this model system. All animals that were promoted with TPA for the same duration had a similar incidence of papillomas (pap) regardless of radiation or TPA pretreatment. However, squamous cell carcinomas (scc) arose only in animals that were initiated with ionizing radiation followed by TPA promotion. Increasing the promotion duration enhanced the incidence of scc at the lower initiation dose. TPA pretreatment at the higher irradiation dose resulted in an overall decrease in tumor incidence. At the lower dose of radiation, TPA pretreatment resulted in an increase in the incidence of scc. The incidence of basal cell carcinomas (bcc) was dose dependent and appeared to be independent of TPA promotion. Although ionizing radiation acts as a weak initiator in mouse skin, the conversion of pap to scc was higher than that reported for chemical initiators. To test this further animals were initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) followed by biweekly promotion with TPA. After 20 weeks of promotion, the animals were treated with either acetone, TPA or 8 fractions of 1 MeV electrons. Data indicate that the dose and fractionation protocol used in this study enhanced the progression of pre-existing pap. To examine the role of oncogene activation in radiation induced mouse skin tumors, DNA from various tumors (pap, bcc, scc) were examined for the presence of dominant transforming activity by the NIH3T3 and Rat-2 focus assays. Dominant transforming activity was observed in all tumor types but not in normal or treated epidermis or corresponding liver. The transformed phenotype was further confirmed by growth in soft agar and tumorigenicity in Nude mice. Southern blot hybridization to ras (Ha, Ki, N), raf, neu, erbB and β-lym indicate that these genes are not responsible for the observed transforming activity. These data suggest that the oncogenic sequences activated in these tumors are unique. The work presented here also provides evidence for novel c-myc transcripts and corresponding genomic rearrangements in a few of the tumors studied.

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