valproic acid + karenitecin

A combination of the histone deacetylase inhibitor valproic acid and the camptothecin analog topoisomerase I inhibitor karenitecin, investigated to enhance antitumor activity in melanoma by potentiating DNA damage. Preclinical studies showed valproic acid pretreatment increases karenitecin-induced DNA strand breaks and apoptosis, and a phase I/II trial in metastatic melanoma found the combination tolerable with somnolence as the dose-limiting toxicity and disease stabilization in a subset of patients.[2] In the trial, valproic acid at 75 mg/kg/day for 5 days achieved histone hyperacetylation and could be combined with full-dose karenitecin without overlapping toxicities; at expansion, 47% of patients had stable disease with median overall survival 32.8 weeks and time to progression 10.2 weeks.[1][2] Reviews of karenitecin note activity as a single agent and synergistic interaction with HDAC inhibitors such as valproic acid leading to clinical evaluation of this schedule-specific combination.[3]

Other names

VPA + KTN