Multiple myeloma (MM) is a uniformly fatal disease. Current therapies provide short-term palliation. Consequently, new approaches to the treatment of MM are needed. The applicant has recently observed that a novel nucleoside analog, 8-Chloro-Adenosine (8Cl-AD), is very effective in promoting programmed cell death in a number of MM cell lines that are resistant to traditional chemotherapeutic agents. Encouraged by initial in vitro results, the NCI has awarded the laboratory a RAID grant for large scale production of 8Cl-AD and to collaboratively perform in vivo analysis. Nucleosides with closely related structures exhibit cellular metabolic characteristics and action mechanisms that vary widely. Most impressively, it is clear that nucleoside analogs with closely related structures, that share metabolic pathways, and inhabit similar target enzymes, still exhibit a diverse spectrum of anticancer activity in human tumor types in the clinic. Hence, understanding the metabolism and actions of any drug is requisite to optimizing its clinical utility. Here, the mechanism of action for 8Cl-AD will be elucidated. Preliminary data support that this purine analog preferentially inhibits RNA synthesis. The proposed investigation will address the cellular metabolism and actions of 8Cl-AD using HPLC to measure the accumulation and elimination of 8Cl-AD nucleotides. The applicant will determine if 8Cl-AD has an effect on ribonucleotide reductase activity and he will also explore the inhibitory potency of 8Cl-AD on RNA synthesis. Using chemical and enzymatic methods, he will synthesize DNA and RNA polymers that contain 8Cl-AD to determine the biological impact on DNA and RNA biosynthesis. He will examine key steps in the induction of apoptosis including mitochondrial injury and caspase activation to determine if those steps are regulated by 8Cl-AD. He anticipates that these studies will allow us to maximize the therapeutic potential of this agent against MM and related malignancies.
Showing the most recent 10 out of 36 publications
