locally-acting temozolomide formulation SI-053

A powder for gel formulation containing the cytotoxic alkylating agent temozolomide (TMZ), an imidazotetrazine derivative of the alkylating agent dacarbazine, immobilized on the polymeric carrier dextran phosphate, with potential antineoplastic activity. The TMZ formulation SI-053 forms a viscous gel upon reconstitution in water. Upon local intraoperative administration of the gel into the cavity that is formed after resection of the brain tumor, SI-053 allows for local and prolonged action of TMZ. TMZ is converted at physiologic pH to the short-lived active compound 5-(3-methyl-(triazen-1-yl)-imidazole)-4-carboxamide (monomethyltriazenoimidazole carboxamide; MTIC). The cytotoxicity of MTIC is due to methylation of DNA, particularly at the O6 and N7 positions of guanine residues, resulting in cell cycle arrest, inhibition of DNA replication and the induction of apoptosis. The local administration of TMZ allows for the local destruction of the remaining tumor cells immediately after the removal of the tumor and may prevent the recurrence of tumor growth while having no severe systemic toxicity.