Dissertation

Strategies to enhance the efficacy of alkylating agent chemotherapy

Middleton, Mark Ross

2000

Overview

There is substantial evidence to indicate that the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) plays a major role in cellular resistance to the cytotoxic effects of O6-alkylating agent chemotherapies, including temozolomide. Depletion of ATase in tumours prior to treatment might therefore be expected to improve clinical outcomes with these drugs. In the first part of this thesis the relationship between melanoma ATase expression and response to temozolomide was examined. No correlation was found, but heterogeneity tumour ATase expression and downstream resistance mechanisms might account for this. Altering the schedule of temozolomide to allow dosing at the ATase nadir following prior administration might enhance the drug's activity. This was explored in an animal model, where 4-hourly administration of temozolomide delayed melanoma xenograft growth significantly more than the standard 24- hourly dosing regimen. Increased tumour DNA methylation, compared with standard therapy, was observed with the compressed schedule, and might be the basis for the increased anti-tumour effect. However, toxicity was also increased making it unclear if an improvement in therapeutic index could be achieved. A clinical trial in melanoma patients established that the response rate with temozolomide was increased, but at the expense of increased haematological toxicity. Tumour and peripheral blood mononuclear cell DNA methylation were increased compared with standard treatment regimens. Pre-treatment peripheral blood mononuclear cell ATase predicted for haematological toxicity, a fmding borne out with other schedules of temozolomide administration. Indirect inactivation of ATase via cytotoxic agents has yielded little clinical benefit, so interest has turned to non-toxic pseudosubstrate inactivators of the protein. One such inactivator, O6-(4-bromothenyl)guanine (4BTG), was tested in combination with temozolomide in a number of animal tumour models. 4BTG enhanced the effect of temozolomide against a range of tumours, with little or no additional toxicity. 4BTG also appeared to attenuate the development of resistance to temozolomide in xenografts. The biodistribution of 4BTG was studied using radiolabelled compound. These studies have established that compressed scheduling of temozolomide, whilst improving response rates, is of limited clinical use due to increased toxicity. Direct ATase inactivation using 4BTG holds more promise, and the combination of 4BTG and temozolomide is now in clinical trials.

• Publisher: ProQuest Dissertations & Theses
• Subject: Oncology / Pharmacology
• ISBN: 0355584727, 9780355584721