Many patients with
acute myeloid leukemia (AML) are still dying from this disease. In the past, the
alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of
O6-methylguanine DNA methyltransferase (MGMT;
a DNA repair
enzyme) in
tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called
NEO212, where TMZ was covalently conjugated to
perillyl alcohol (a naturally occurring
monoterpene).
NEO212 has revealed robust therapeutic activity in a variety of preclinical
cancer models, including AML. In the current study, we investigated its impact on a panel of human AML cell lines and found that it exerted cytotoxic potency even against MGMT-positive cells that were highly resistant to TMZ. Furthermore,
NEO212 strongly stimulated the expression of a large number of macrophage-associated marker genes, including CD11b/ITGAM. This latter effect could not be mimicked when cells were treated with TMZ or an equimolar mix of individual agents, TMZ plus
perillyl alcohol. The superior cytotoxic impact of
NEO212 appeared to involve down-regulation of MGMT
protein levels. In a mouse model implanted with TMZ-resistant, MGMT-positive AML cells, two 5-day cycles of 25 mg/kg
NEO212 achieved an apparent cure, as mice survived >300 days without any signs of disease. In parallel toxicity studies with rats, a 5-day cycle of 200 mg/kg
NEO212 was well tolerated by these animals, whereas animals that were given 200 mg/kg TMZ all died due to severe
leukopenia. Together, our results show that
NEO212 exerts pleiotropic effects on AML cells that include differentiation, proliferation arrest, and eventual cell death. In vivo,
NEO212 was well tolerated even at dosages that far exceed the therapeutic need, indicating a large therapeutic window. These results present
NEO212 as an agent that should be considered for development as a therapeutic agent for AML.