title: Effect of lonidamine on the cytotoxicity of four alkylating agents in vitro.
abstract: We examined the ability of lonidamine, which has been described as an inhibitor of cellular respiration and glycolysis, to enhance the cytotoxicity of alkylating agents to MCF-7 human breast-carcinoma cells. Lonidamine was increasingly cytotoxic to MCF-7 cells with increasing time of exposure. With a 12-h exposure, the IC50 for lonidamine was about 365 microM, and with a 24-h exposure it was about 170 microM. A drug concentration of 250 microM was chosen for use in the drug combination studies. Lonidamine appeared to have a dose-modifying effect on cisplatin (CDDP), producing increasingly supra-additive cell kill with increasing CDDP concentration. When simultaneously incubated with lonidamine for 1 h, 500 microM CDDP yielded a cell kill that was 2 log greater than additive cytotoxicity. Extending the exposure to lonidamine for 12 h after CDDP treatment led to a small, additional aliquot of cell kill of about 2.5-fold over the CDDP concentration range. Lonidamine also appeared to have a dose-modifying effect on melphalan cytotoxicity in the melphalan concentration range of 100-500 microM. Between concentrations of 10 and 100 microM melphalan, the drug combination survival after 1 h exposure fell within the envelope of additivity for the two agents. However, maintaining the presence of lonidamine for an additional 12 h increased the effect such that the combination was supra-additive over the entire concentration range of melphalan. Simultaneous exposure to 4-hydroperoxycyclophosphamide (4-HC) and lonidamine for 1 h resulted in greater than additive cell kill, and extending the lonidamine exposure period such that lonidamine was present during and 12 h after 4-HC treatment further increased this effect. Lonidamine had a moderate effect on the cytotoxicity of carmustine (BCNU) with a 1 h simultaneous exposure; however, this treatment combination reached greater than additive cytotoxicity only at the highest concentration of BCNU tested. Extending the lonidamine exposure time for an additional 12 h resulted in supra-additive cell kill over the BCNU concentration range. Therefore, when lonidamine was present during exposure to the alkylating agent and its presence was then extended for an additional 12 h, a synergistic cell kill was produced with all four alkylating agents tested.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: K W
authors.initials: KW
authors.lastname: Rosbe
authors.forename: T W
authors.initials: TW
authors.lastname: Brann
authors.forename: S A
authors.initials: SA
authors.lastname: Holden
authors.forename: B A
authors.initials: BA
authors.lastname: Teicher
authors.forename: E
authors.initials: E
authors.lastname: Frei
mesh_terms: D000477:Alkylating Agents / Q000627:therapeutic use / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use / Q000633:toxicity*; D011720:Pyrazoles / Q000633:toxicity*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D007191:Indazoles; D011720:Pyrazoles; C016371:lonidamine