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DNA repair and the cytotoxic effects of cisplatin and DNA thiobases

Massey, Andrew James; (2001) DNA repair and the cytotoxic effects of cisplatin and DNA thiobases. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

DNA Mismatch Repair (MMR) modulates the cytotoxicity of the therapeutic agent cisplatin. Two model systems: cisplatin sensitive Escherichia coli dam mutants and the ovarian carcinoma cell line A2780 were used to investigate the possible selection of MMR defects in cisplatin resistance. Cisplatin sensitivity in dam mutants is partially reversed by a mutation in either the mutS or mutL MMR genes. Bacteria selected for cisplatin resistance were either dam revertants or dam mmr mutants. The latter displayed a partial decrease in sensitivity although some variants were comparable to wild type in this respect. This suggests the contribution of additional factors to cisplatin resistance. Several independently selected variants of the ovarian tumour line A2780 were 1.5 to 3-fold less sensitive to cisplatin. All were proficient for mismatch repair. Two factors were identified that contributed to resistance - reduced levels of platination indicative of a protective mechanism and possible defects in p21 induction after cisplatin treatment. Thiopurines are used in the treatment of leukaemia. Active DNA mismatch repair is required for 6-thioguanine (S6G) toxicity. S6G is incorporated into DNA and requires in vivo methylation at the S-6 position for lethality. The deoxynucleoside, 4-thiothymidine (S4TdR), was evaluated as a potential chemotherapeutic agent. S4TdR was incorporated into DNA and was S-methylated. Unlike S6G, it showed no mismatch repair dependent toxicity. DNA S4meT does not code ambiguously during replication. This property probably underlies its failure to interact with MMR. S4TdR absorbs light in the UVA range. UVA was synergistically toxic to human cells grown in S4TdR. The thiopyrimidine sensitised normal fibroblasts approximately 100-fold to UVA. DNA adducts, possibly resembling (6-4) pyrimidine pyrimidone photoproducts, are implicated in this synergistic toxicity because S4TdR conferred a 1000-fold sensitisation to UVA light in nucleotide excision repair deficient fibroblasts. Both S6G and S4dUdR also display synergistic cytotoxicity with UVA. The photochemical properties of thiobases may offer a novel therapeutic option.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: DNA repair and the cytotoxic effects of cisplatin and DNA thiobases
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Cisplatin resistance
URI: https://discovery.ucl.ac.uk/id/eprint/10104007
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