Pamidronate and 1,24(S)-dihydroxyvitamin D2 synergistically inhibit the growth of myeloma, breast and prostate cancer cells

Background: Bisphosphonates have proven to be effective in the management of multiple myeloma and bone metastases secondary to breast and prostate carcinoma. Vitamin D compounds are important modulators of cellular proliferation and differentiation. 1,24(S)-dihydroxyvitamin D2 (1,24(OH)2D2) is a naturally occurring active vitamin D compound with high antiproliferative activity and low calcemic response. Materials and Methods: We examined the antiproliferative effects of 1,24(OH)2D2 in combination with the bisphosphonate pamidronate on multiple myeloma (H929), prostate (LNCaP) and breast (MCF-7) cancer cell lines. Drug-drug interactions were analyzed using the median- effect/isobologram method to characterize the interactions as synergistic, additive, or antagonistic. Results: Pamidronate and 1,24(OH)2D2 were found independently to inhibit cancer cell growth in a dose-dependent manner. Combinations of these compounds produced marked synergistic growth-inhibitory effects at several clinically relevant concentrations. Conclusion: Combined dosing of pamidronate and 1,24(OH)2D2 may have therapeutic value for the treatment of multiple myeloma, prostate and breast cancers. Osteolysis, fractures, bone pain and hypercalcemia of malignancy are all tumor-associated skeletal complications resulting from cancers of breast, prostate and multiple myeloma. Although the molecular mechanisms of these complications are not completely understood, it is believed that tumor cells adhere to bone extracellular matrix or bone marrow microenvironments, and release soluble factors that stimulate abnormal osteoblast activity and osteoclast- mediated bone resorption at these adhesion sites (1-3). High morbidity and mortality rates indicate that new and more effective treatment strategies are essential to improve patient outcomes in these cancer populations (4).