Cytotoxicity of etidronic acid to human breast cancer cells.
BACKGROUND
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.
Zhou
Yanfei
Y
Department of Radiation Oncology, Cancer Center, College of Medicine, Howard University, Washington, DC. 20060, USA.
Beyene
Desta
D
Zhang
Renshu
R
Kassa
Alemayehu
A
Ashayeri
Ebrahim
E
Sridhar
Rajagopalan
R
D050071:Bone Density Conservation Agents / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D012968:Etidronic Acid / Q000633:toxicity*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D016133:Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
D050071:Bone Density Conservation Agents; D016159:Tumor Suppressor Protein p53; D012968:Etidronic Acid