Chapter 28 - MGMT Stem Cell Selection and Protection: Preclinical Large Animal and Clinical Studies

Abstract

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