C8-Substituted Imidazotetrazine Analogs Overcome Temozolomide Resistance by Inducing DNA Adducts and DNA Damage.

ABSTRACT: Temozolomide (TMZ) is the standard of care chemotherapeutic agent used in the treatment of glioblastoma multiforme. Cytotoxic O6-methylguaine lesions formed by TMZ are repaired by O6-methyl-guanine DNA methyltransferase (MGMT), a DNA repair protein that removes alkyl groups located at the O6-position of guanine. Response to TMZ requires low MGMT expression and functional mismatch repair. Resistance to TMZ conferred by MGMT, and tolerance to O6-methylguanine lesions conferred by deficient MMR severely limit TMZ clinical applications. Therefore, development of new TMZ derivatives that can overcome TMZ-resistance is urgent. In this study, we investigated the anti-tumor mechanism of action of two novel TMZ analogs: C8-imidazolyl (377) and C8-methylimidazole (465) tetrazines. We found that anal

SUBMITTER: Yang Z 

PROVIDER: S-EPMC6584802 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature