Preclinical evaluation of Laromustine for use in combination with radiation therapy in the treatment of solid tumors

Purpose: These studies explored questions related to the potential use of Laromustine in the treatment of solid tumors and in combination with radiotherapy. Materials and methods: The studies used mouse EMT6 cells (both parental and transfected with genes for O⁶-alkylguanine-DNA transferase [AGT]), repair-deficient human Fanconi Anemia C and Chinese hamster VC8 (BRCA2^-/-) cells and corresponding control cells, and EMT6 tumors in mice assayed using cell survival and tumor growth assays. Results: Hypoxia during Laromustine treatment did not protect EMT6 cells or human fibroblasts from this agent. Rapidly proliferating EMT6 cells were more sensitive than quiescent cultures. EMT6 cells expressing mouse or human AGT, which removes O⁶-alkyl groups from DNA guanine, thereby protecting against G-C crosslink formation, increased resistance to Laromustine. Crosslink-repair-deficient Fanconi Anemia C and VC8 cells were hypersensitive to Laromustine, confirming the importance of crosslinks as lethal lesions. In vitro, Laromustine and radiation produced additive toxicities to EMT6 cells. Studies using tumor cell survival and tumor growth assays showed effects of regimens combining Laromustine and radiation that were compatible with additive or subadditive interactions. Conclusions: The effects of Laromustine on solid tumors and with radiation are complex and are influenced by microenvironmental and proliferative heterogeneity within these malignancies. (authors)