Effect of lonidamine on the cytotoxicity of four alkylating agents in vitro

• Published in: Cancer chemotherapy and pharmacology Vol. 25; no. 1; p. 32
• Main Authors: Rosbe, K W, Brann, T W, Holden, S A, Teicher, B A, Frei, 3rd, E
• Format: Journal Article
• Language: English
• Published: Germany 1989
• Subjects: Alkylating Agents - therapeutic use; Alkylating Agents - toxicity; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - toxicity; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Carcinoma - drug therapy; Carcinoma - pathology; Cell Line - drug effects; Cell Line - pathology; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Indazoles - therapeutic use; Indazoles - toxicity; Pyrazoles - toxicity; Time Factors; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - pathology
• ISSN: 0344-5704
• DOI: 10.1007/BF00694335

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.