ABSTRACT
With what has become increasingly common among nearly all medical specialties, the number of patients who have various comorbid diseases both psychiatrically and mentally challenges the field of psychiatry. As a result, it is not uncommon for physicians to be imposed with treatment decisions regarding polypharmacy, the use of multiple medications to treat different diseases, or even the same illness several times. In recent years, the concept of polypharmacy has been known to have a negative undertone, implying that its use is inappropriate or causes more harm than the potential benefit. Although the use of any medication should involve risk versus benefit discussion, when used with good clinical judgment and pharmacologically sound knowledge, this practice can be potentially life-altering for patients.
Subject(s)
Polypharmacy , HumansABSTRACT
Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies.