Sequential Doxorubicin And Zoledronic Acid Have Powerful Anti-Tumor Effect In Vivo

Zoledronic acid is a bisphosphonate currently used for the treatment of cancer-related bone disease in a variety of malignancies, including breast cancer. Breast cancer patients are also frequently treated with the anthracycline doxorubicin. Previous preclinical studies have suggested that the combination of doxorubicin and zoledronic acid may reduce tumor growth in models in which bone disease is prominent.

To determine what impact the combination might have on breast cancer tumors in the absence of bone disease, Ingunn Holen, Ph.D., of the University of Sheffield, UK, and colleagues injected animals with breast cancer cells that do not readily metastasize to bone. They subsequently treated animals with each agent alone, the two agents given simultaneously, zoledronic acid followed 24 hours later by doxorubicin, or doxorubicin followed 24 hours later by zoledronic acid.

There was no difference in tumor size following treatment with either single agent or with zoledronic acid followed by doxorubicin, as compared with animals treated with saline. Tumor size was approximately halved in animals treated with the two drugs dosed simultaneously compared with animals treated with doxorubicin alone. However, the largest reduction in tumor growth occurred in animals treated with doxorubicin followed by zoledronic acid, which resulted in nearly complete destruction of the tumors. Sequential therapy with doxorubicin and zoledronic acid was shown to increase the fraction of tumor cells undergoing cell death and reduce the number of dividing cells.

"To our knowledge, this is the first report to show that doxorubicin and zoledronic acid inhibit subcutaneous breast tumor growth in vivo in a treatment sequence–specific fashion and in the absence of tumor-induced bone disease," the authors write. "Our data suggest that there may be benefits of combining zoledronic acid with cytotoxic agents for the treatment of patients with early-stage breast cancer."