Cytotoxicity of etidronic acid to human breast cancer cells.

INTRODUCTION: Bisphosphonates have been used to treat Paget's disease, osteoporosis, and cancer metastases to the bone. The cancer chemotherapeutic potential of a first-generation bisphosphonate, etidronic acid, was evaluated by using MCF-7 human breast cancer cells.

METHODS: In vitro cytotoxicity of etidronic acid to MCF-7 cells was estimated on the basis of clonogenicity assays, while cell cycle effects were determined by using flow cytometry. Mutagenicity of etidronic acid was detected by using denaturing high-pressure liquid chromatography analysis of cellular DNA amplified by PCR with primers for exons 5 through 8 of the human p53 gene.

RESULTS: A 24-hour treatment with etidronic acid (10 mM) with or without strontium chloride was cytototoxic to MCF-7 cells. Etidronic acid caused a decrease in the S-phase population and an increase in the G2/M population. Mutations in the p53 gene were detected in MCF-7 cells treated with etidronic acid. Strontium chloride was not cytotoxic to cells.

CONCLUSIONS: Cytotoxicity of etidronic acid to breast cancer cells may complement its inhibitory effects on bone resorption at the site of bone metastasis. Within the cell cycle, late S-phase cells are the most radioresistant, while cells at the G2/M border are the most sensitive. Therefore the decrease in S-phase population with corresponding increase in G2/M would make the cells more radiosensitive. This may be useful if etidronic acid were combined with radioactive strontium (89Sr, metastron) or external-beam radiotherapy for treating bone metastases. Tumor cells that survive etidronic acid treatment may acquire drug resistance because of mutations in the p53 tumor-suppressor gene.