Advances in the pharmacological management of acute myeloid leukemia in adults

Numan, Yazan; Abaza, Yasmin; Altman, Jessica K.; Platanias, Leonidas C.

doi:10.1080/14656566.2022.2111212

Cited by 1 publication

(1 citation statement)

References 123 publications

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“…First-line treatment consists of chemotherapy, which typically is separated into an induction and consolidation (postremission) phase. The induction phase generally uses cytarabine (AraC) in combination with an anthracycline such as daunorubicin, or high-dose AraC alone, although more recently alternative treatments have been introduced, primarily for “fit” patients with better performance status [ 1 , 2 ]. After complete remission is achieved, drug composition of the subsequent consolidation therapy is variable and individualized based on prognostic factors, including tumor cytogenetics and general health of the patient, and may include further chemotherapy and stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity

Chen

Minea

Swenson

et al. 2022

Cancers

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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.

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Section: Introductionmentioning

confidence: 99%