Sullivan, Dianne Clare; (2001) Thioguanine toxicity. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The toxic action of the anticancer drug thioguanine is believed to involve incorporation into DNA, methylation by S-adenosylmethionine followed by binding of the resulting S6-methylthioguanine residues by proteins of the post-replicative mismatch repair pathway. S-adenosylmethionine is a very weak methylating agent and methylates only a fraction of the thioguanine residues in DNA. If the proposed mechanism of toxicity were correct, a more powerful methylating agent would be expected to increase the cytotoxicity of thioguanine. The work in the first part of this thesis aimed to determine whether cytotoxic synergy between thioguanine and methylating agents could be demonstrated. Using nude mouse xenografts models for glioblastoma and for melanoma, synergy between thioguanine and the clinically used methylating agent temozolomide was demonstrated. This synergy between thioguanine and temozolomide could not be reproduced in tissue culture, however there was synergy between thioguanine and the methylating agent methyl methanesulphonate. Investigation suggested that the difference between the cytotoxicity of these two methylating agents when given after thioguanine is a reflection of differences in their chemistry. It was found that methyl methanesulphonate which acts by an SN2 mechanism reacts much more with the 6-S of thioguanine residues in DNA than do methylating agents which, like temozolomide react by an SN1 mechanism. It is known that treatment of cells with compounds giving O6-methylguanine in DNA can produce cells that are deficient in post-replicative mismatch repair therefore it is possible that thioguanine could also produce deficient cells. Production of MMR deficient cells might contribute to the high incidence of skin cancer and leukaemia associated with thioguanine. Cells in tissue culture were treated with non toxic concentrations of thioguanine followed by selection of post-replicative mismatch repair deficient cells. Some of the deficient cells were found to lack the hMLH1 protein of the post-replicative mismatch repair system. The absence was not due to a mutation in the gene but because of silencing of the promoter region, a common feature of sporadic colorectal cancers.

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