Methoxyamine (MX, NSC-3801) is a novel compound that inhibits base excision repair (BER), an important DMA repair pathway, by covalently binding to apurinic/apyrimidinic (AP) sites in DMA. BER has been shown to reduce the cytotoxicity of alkylating agents. MX has been studied as a structural modulator of AP sites and in preclinical models has been shown to enhance the therapeutic efficacy of alkylating agents, such as Temozolomide (TMZ, NSC-362856), with a wide therapeutic range. Based on preclinical efficacy and toxicity profile, further development of MX, the first BER inhibitor entering clinical development, is proposed: -In specific aim 1, we propose to conduct a phase I trial in patients with solid tumors to determine the maximum tolerated doses and the dose limiting toxicities of the combination of MX and TMZ. -In specific aim 2, we propose to determine the pharmacokinetics and the biological activity of the combination of MX and TMZ when these two agents are given alone and in combination. Biological activity will be demonstrated by proposed laboratory correlative studies including: i. Measurement of apurinic/apyrimidinic (AP) sites in blood mononuclear cells, with an expected drop of at least 40% in detectable apurinic/apyrimidinic (AP) sites in blood mononuclear cells following treatment with the combination of methoxyamine and temozolomide compared to temozolomide alone. ii. Determination of the DMA strand breaks by comet assay in blood mononuclear cells, with an expected greater than two-fold increase of the detected single and double stranded DMA breaks following treatment with the combination of methoxyamine and temozolomide compared to temozolomide alone. Clinical development of MX has the potential to improve outcomes of patients treated with alkylating chemotherapeutic agents for various malignancies by inhibiting one of the mechanisms of DMA repair used by tumor cells to overcome the cytotoxic effect of alkylating chemotherapeutics. ? ? ?
| Yang, Shuming; Savvides, Panayiotis; Liu, Lili et al. (2012) Development and validation of an LC-MS/MS method for pharmacokinetic study of methoxyamine in phase I clinical trial. J Chromatogr B Analyt Technol Biomed Life Sci 901:25-33 |
