MGMT Stem Cell Selection and Protection: Preclinical Large Animal and Clinical Studies

摘要: Temozolomide (TMZ) and N,N′-bis(2-chloroethyl)-N-nitroso-urea (BCNU) are alkylating agents used as chemotherapy to treat many different types of cancer. Combined administration these with the wild-type O6-methylguanine methyltransferase (MGMT) nucleoside inhibitor, O6-benzylguanine (O6-BG), potentiates cytotoxicity in tumour cells but also results exacerbating dose-limiting hematopoietic toxicity. Viral vector-mediated gene transfer O6-BG-resistant mutant MGMT, P140K, can provide chemoprotection well a means select stably increase level gene-modified blood vivo. This chapter discusses application this strategy preclinical large animal studies, including canine nonhuman primate models, phase I clinical trials cancer patients. These studies have demonstrated feasibility approach multiple viral vectors both autologous allogeneic transplant settings myeloablative reduced-intensity conditioning regimens, emphasizing potential applications not only facilitate treatment genetic infectious disease affecting various subsets.