Laromustine (
Onrigin), under development by Vion
Pharmaceuticals Inc, belongs to the sulfonylhydrazine class of
alkylating agents and is in clinical development for the treatment of
malignancies.
Laromustine is a
prodrug that yields a chloroethylating compound (VNP-4090-CE) and a carbamoylating compound (
methyl isocyanate). The
antineoplastic effect of
laromustine is attributed primarily to the chloroethylating species, which causes the preferential alkylation of
DNA at the O6 position of
guanine, a lesion that results in interstrand crosslinks and, eventually, cell death. The carbamoylating species contributes to antitumor activity by inhibiting the DNA repair
protein O6-alkylguanine
transferase. Early phase I clinical trials in patients with solid
tumors indicated that
laromustine was associated with myelosuppression; few extramedullary toxicities were observed, indicating potential efficacy for the treatment of
hematological malignancies. Phase II trials have been completed in patients with previously untreated
acute myelogenous leukemia (AML), high-risk
myelodysplastic syndrome (MDS) and relapsed AML. The most encouraging results were observed in patients over 60 years of age with poor-risk de novo AML for which no standard treatment exists.
Laromustine is currently in phase II/III trials for AML and phase II trials for MDS and solid
tumors.
Laromustine appears to be a promising agent that will add to the armamentarium of drugs available to treat patients who do not respond to, or are not fit for, intensive
chemotherapy, such as elderly individuals.