Patients with advanced prostate cancer (CaP) suffer from the severe consequences of hormone-refractory disease and bone metastases. After development of metastatic hormone-refractory disease, CaP is incurable, with a median survival of 9 to 12 months. Given the near-certainty that processes associated with hormone-refractory CaP and bone metastasis contribute directly to morbidity (pain, bone fractures, bone marrow failure) of patients, treatment modalities that would eliminate the advanced disease, slow down progression, or improve the quality of life of patients with advanced CaP are of great interest. Hormonal therapy, radiotherapy, and chemotherapy do not cure hormone-refractory disease . Attacking the tumor cells by multiple mechanisms may prove to be much more effective in killing tumor cells; therefore combined chemotherapies are one of the most promising themes of today's clinical picture.
Zoledronic acid (ZOL) is one of the most potent of the new-generation bisphosphonates (BPs), compounds that inhibit bone lysis and have been used in the treatment of bone diseases and bone metastastatic disease [2–7], and stimulate apoptosis in cancer cells [8–10]. Effects of ZOL on tumor cells [11, 12], including prostate tumors [13–19], have been reported in the literature. In our previous in vivo studies we have shown that growth of subcutaneous CaP tumors was not inhibited by ZOL; however, growth of prostate cancer cells in the bone environment was significantly inhibited, but the tumors were not eradicated . We have also shown that the probable mechanisms of the effects of ZOL on tumor in bone are indirect, via its effects on bone cells . The value and potential of ZOL in treatment of patients with cancer-related bone disease were reviewed , and a large number of reports have recently documented the benefits of ZOL treatment in patients with advanced prostate cancer [20–31]. However, in parallel with our pre-clinical study, these published results suggest that BPs can slow progression of the disease, but a cure is not achieved. Therefore, combinations of BPs with other agents such as chemotherapeutic drugs to control tumor growth while regulating tumor-induced bone remodeling have appeared as a promising new treatment strategy.
Docetaxel, an inhibitor of tubulin depolymerization, has emerged as the most valuable chemotherapeutic treatment for advanced CaP. Phase II studies have shown decreased prostate specific antigen (PSA) levels and increased survival, with dosage amounts and regimens varying from 25–75 mg/m2 every 1 or 3 weeks [32–37]. However, the toxicity of this treatment is significant and complete cures are still not achieved .
The recent history of chemotherapy has shown that with difficult disease targets, combinatorial therapy frequently offers the best chance of a cure. Therefore testing of combinations of BPs with other agents is of significant interest in the treatment of various cancers. Many of the initial studies of BPs in combination with chemotherapy were conducted on breast cancer or myeloma, where the bone lesions are highly osteolytic. Combinations of taxoids with BPs in vitro exhibited additive anti-tumor effects against invasion and adhesion  and induction of apoptosis in breast-cancer cells in vitro  and in vivo . Moreover, inclusion of BPs in standard chemotherapy has led to a sustained reduction in skeletal complications in breast-cancer patients [41–43]. In advanced CaP patients, ZOL in combination with docetaxel and low-dose estramustine phosphate was recently shown to decrease serum PSA and pain levels . Additionally, Vordos et al. reported that ZOL in combination with docetaxel decreased serum PSA by over 50% at 2 months in more than half of the patients . It has also been reported that the alendronate in combination with taxol is more effective in preventing development of bone metastases in a CaP animal model than either therapy independently .
In this study we used a combination of ZOL and docetaxel to evaluate changes in bone remodeling and tumor growth of an osteoblastic CaP xenograft, LuCaP 23.1.