Article

Laromustine, a sulfonyl hydrolyzing alkylating prodrug for cancer therapy

Service des Maladies du Sang, Centre François Magendie, Hôpital Haut-Lévêque, Avenue de Magellan, 33604 Pessac CEDEX, France.
IDrugs: the investigational drugs journal (Impact Factor: 2.33). 02/2009; 12(1):39-53.
Source: PubMed

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.

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