Purpose: A major mechanism of resistance to temozolomide involves the DNA repair protein O 6 -alkylguanine-DNA-alkyltransferase (ATase). The main aims of this phase I trial were to determine an ATase-depleting dose (ADD) of lomeguatrib, a potent pseudosubstrate inhibitor, and to define a suitable dose of temozolomide to be used in combination with lomeguatrib in patients with advanced cancer. Experimental Design: Lomeguatrib was administered at dose levels of 10 to 40 mg/m 2 days 1to 5, as a single agent, and also in combination with temozolomide. Once theADD of lomeguatrib was identified, the dose of temozolomide in combination was increased, in successive patient cohorts, from 50 to 175 mg/m 2 on days 1to 5 of a 28-day cycle to define the maximal tolerated dose and dose-limiting toxicity of the combination. Results: Thirty-eight patients with advanced solid tumors were enrolled. More than 95% ATase depletion within 4 hours of the first dose was achieved in peripheral blood mononuclear cells at lomeguatrib doses of z10 mg/m 2 /d i.v. or z20 mg/m 2 /d orally, and tumor biopsies showed z92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m 2 days 1to 5. The dose limiting toxicity of the combination of lomeguatrib and temozolomide was myelosuppression. The toxicity of lomeguatrib alone was minimal. In 23 patients with measurable disease, one complete response was seen and12 patients had stable disease for at least 3 months. Conclusion:This first administration of lomeguatrib to man successfully established an oral ADD of lomeguatrib and identified a combination regimen with temozolomide suitable for future clinical evaluation.

A number of novel guanine derivatives containing heterocyclic moieties at the O6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O6-substituents were investigated in which the benzene ring of the known agent, O6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O6-benzylguanine. The present paper focuses on O6-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O6-substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12), 5-bromothenyl (17), and 2-chloro-4-picolyl (21) derivatives.

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