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The cytochromes P450 (CYPs), epoxide hydrolases (EHs) and glutathione S-transferases (GSTs) are three of the major families of enzymes involved in the metabolism of xenobiotics in the human body. Immunohistochemical analysis revealed a high frequency of expression of xenobiotic metabolising enzymes in all tumour types studied, in contrast to corresponding normal tissue which displayed only low levels of expression. Further examination of the CYP1 family was carried out by immunoblot analysis. All breast tumours studied were found to express CYP1B1, and not CYP1A1 or CYP1A2. Moreover, CYP1B1 was identified in a number of kidney tumours but not in corresponding normal kidney, indicating that CYP1B1 may be a tumour-specific form of CYP, RT-PCR, in combination with restriction digestion and DNA sequencing, was used to identify CYP mRNA species present in several tumour types. Although CYP1A1 mRNA was identified in breast carcinomas, CYP1B1 was found to be the most frequently expressed form of the CYP1 family in this tissue. CYP3A mRNA was also displayed by several breast tumours, and demonstrated by sequencing to be CYP3A5. A similar situation to breast tumours was observed in tumours of the gastro-intestinal and urinary tracts, with CYP1B1 being the most frequently expressed form of the CYP1 family, and only a small number of samples displaying evidence of CYP1A mRNA. The effects of the expression of xenobiotic metabolising enzymes in tumours may be complex, and depend upon the relative amounts of active protein present, but it is likely that they will exert an influence on both the development of carcinogenesis and the anti-cancer drug resistance of tumours.

Doctor of Philosophy(PhD) / The present study deals with the synthesis, characterization, determination of anticancer activity of three mononuclear trans-planaraminepalladium(II) complexes code named TH5, TH6 and TH7 and three trinuclear complexes code named TH1, TH8 and TH14. The activity of the compounds against human cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, DNA-binding and nature of interaction with pBR322 plasmid DNA have been determined. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH5, TH6, TH7, TH1 and TH8 bind with DNA forming mainly interstrand GG adducts that causes more of a global change in DNA conformation. Although TH5, TH6 and TH7 each have two substituted pyridine ligands in a trans-geometry (3-hydroxypyridine in TH5, 2-hydroxypyridine in TH6 and 4-hydroxypyridine in TH7), the compounds differ in their activity against ovarian cancer cell lines, indicating that non-covalent interactions involving the hydroxyl group may be playing a significant role in activity of the compounds. Among trinuclear complexes TH1 is found to be significantly more active than cisplatin. It is actually twice as active as cisplatin against the parent cell line A2780, thirteen times as active as cisplatin against the cisplatin-resistant cell line A2780cisR and 11.5 times as active as cisplatin against the cell line A2780ZD0473R. Whereas the resistance factor for cisplatin as applied to the cell lines A2780 and A2780cisR cell lines is 12.9 that for TH1 is 1.98. The results suggest that TH1 has been able to significantly overcome resistance operating in A2780cisR cell line. The compound is soluble in water so that it may be taken orally. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin. Although platinum drugs use a shot-gun approach to kill cancerous cells, widespread use in the clinic and increasing volume of their sale indicate that even in the genomic age, there is still need for shot-gun drugs in the clinic.