Laromustine, a sulfonyl hydrolyzing alkylating prodrug for cancer therapy

Abstract

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.