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The irnidazotetrazinones are a novel group of anti tumour agents which have demonstrated good activity against a range of murine tumours and human xenografts. They possess a structure activity relationship similar to the anti tumour triazenes, with the chloroethyl (mitozolomide) and methyl (temozolomide) analogues being active antitumour agents, whilst the ethyl (CCRG 82019) and higher homologues are inactive. This thesiS attempts to elucidate the biological mechanisms responsible for the strict structure-activity relationship observed amongst the imidazotetrazinones. Mitozolomide is the only agent chemically capable of cross-linking DNA , which has been suggested to be responsible fo r the cytotoxicity of this group of agents. Only mitozolomide and ternozolornide Exhibit a marked ditferential toxicity towards the 0 -alkylguanine-DNA alkyltransferase deficient GM892A (Mer-) cell line rather than the proficient Raji cell line (Mer+). The rate of uptake of imidazotetrazinones into cells is similar for all three agents in both cell lines, and does not explain the differing sensitivities to these agents. The effect of drug treatment on the incorporation of precursors into macromolecules, and their pool sizes, was examined. Temozolomide administration was found to alter de novo protein synthesis in both GM892A and Raji cells. Flow cytometric analysis revealed that temozolomide and CCRG 82019 block cells in late S/G2/M phase of the cell cycle , similar to that observed with mitozolomide. The extent of reaction of all three drugs with isolated macromolecules and cellular macromolecules was determined, and differences found, with cellular repair processes influencing the number of alkyl lesions remaining bound to macromolecules. The specific bases formed in calf thymus DNA after treatment with either temozolornide and CCRG 82019 was measured, and it was found that the types and relative amounts of lesions formed, differed, as well as the total level of alkylation. Whereas DNA extracted from imidazotetrazinone treated cells is not affected in its ability to support RNA polymerase activity, an effect is observed on the ability to extract DNA polymerase from drug treated cells. This may suggest that the alkylated DNA must be in intact chromatin for the lesion to manifest its effects. Temozolomide and methyl methanesulphonate do got appear to act with a synergistic mode of action. The 0 -position of guanine is suspected to be a critical site for the action of these types of drugs.

4-Aminobiphenyl is an aromatic amine compound that is present in cigarette smoke, diesel exhaust, cooking oil fumes and dye intermediates. It is a well-known human bladder carcinogen and liver carcinogen in experimental animals that is metabolically activated by liver CYP1A1/2. We have used the “Accelerated Cytotoxicity Mechanism Screening” (ACMS) techniques to analyze the molecular cytotoxic mechanisms of 4-aminobiphenyl. Hepatocyte exposure to an inflammatory system significantly increased hepatocyte susceptibility to 4-aminobiphenyl. 4-Aminobiphenyl- induced cytotoxicity and lipid peroxidation were both prevented by altering cellular redox status and with the addition of antioxidants. Toxicity was increased with the depletion of hepatocyte GSH levels and by inhibiting N-acetyltransferase. These results will provide more insight into the cytotoxic and genotoxic mechanisms of 4-aminobiphenyl and also suggest that inflammation may be responsible for an increase in arylamine carcinogenesis.

4-Aminobiphenyl is an aromatic amine compound that is present in cigarette smoke, diesel exhaust, cooking oil fumes and dye intermediates. It is a well-known human bladder carcinogen and liver carcinogen in experimental animals that is metabolically activated by liver CYP1A1/2. We have used the “Accelerated Cytotoxicity Mechanism Screening” (ACMS) techniques to analyze the molecular cytotoxic mechanisms of 4-aminobiphenyl. Hepatocyte exposure to an inflammatory system significantly increased hepatocyte susceptibility to 4-aminobiphenyl. 4-Aminobiphenyl- induced cytotoxicity and lipid peroxidation were both prevented by altering cellular redox status and with the addition of antioxidants. Toxicity was increased with the depletion of hepatocyte GSH levels and by inhibiting N-acetyltransferase. These results will provide more insight into the cytotoxic and genotoxic mechanisms of 4-aminobiphenyl and also suggest that inflammation may be responsible for an increase in arylamine carcinogenesis.

We have investigated the chemical constituents of the organic extracts of soft coral Lobophytum crassum, collected at Dongsha Atoll. This study has led to the isolation of eight new compounds, including six cembrane-type diterpenoids 1-6 and two a-tocopherol-type compounds 7 and 8 The chemical structures of compounds 1-8 were elucidated by extensive analysis of 1D, 2D NMR spectroscopic data (1H and 13C NMR¡B1H-1H COSY¡BHSQC¡BHMBC¡BNOESY), UV, IR, CD and MS. Compounds 1 and 6 possess unprecedented diterpenoid skeletons. The absolute configurations of compound 1 were determined using a modified Mosher¡¦s method. Compounds 1-8 were tested against A-549 (human lung epithelial carcinoma)¡BHT-29 (human colon adenocarcinoma)¡BP-388 (mouse lymphocytic leukemia) tumor cell lines. Compounds 1, 7, and 8 displayed modest cytotoxicity against P-388 cell line with ED50 values of 3.2, 3.2, and 2.7 £gg/mL, respectively. Compound 8 exhibited marginal cytotoxicity against H-29 cell line with an ED50 value of 3.9 £gg/mL.

Chromatographic separation of methylene chloride extracts of Formosan soft coral Lemnalia laevis, Thomson and Dean (collected at Green Island off Taiwan) led to the isolation of eight sesquterpenoids and three norsesquterpenoids compounds, 4(S¡¯)-acetoxy,10(S¡¯)-hydro xy,5-oxo,1(S¡¯),12(S¡¯)neolemna-2(Z),8-diene (1)¡B4(S*)-acetoxy,10,5-oxo, 1(S*),12(S*)neolemna-1(Z),8-dieme (2)¡B(6