Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment

Abstract

Background: After development of hormone-refractory metastatic disease, prostate cancer is incurable. The recent history of chemotherapy has shown that with difficult disease targets, combinatorial therapy frequently offers the best chance of a cure. In this study we have examined the effects of a combination of zoledronic acid (ZOL), a new-generation bisphosphonate, and docetaxel on LuCaP 23.1, a prostate cancer xenograft that stimulates the osteoblastic reaction when grown in the bone environment.

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

“…2A,B). As we have found previously [38], administration of ZOL alone did not result in decreased levels of serum PSA versus control animals.…”

“…We have recently reported that the combination of ZOL with TAX was more effective than either drug alone in inhibiting growth of CaP in the bone [38], and early clinical studies of this combination have been encouraging [39]. As a logical next step, we have undertaken to add RAD001 to the combination, since this drug affects tumors by an entirely different mechanism.…”

“…Since the efficacy of this agent depends on the tumor type as well as the growth environment [38], we tested two doses of TAX for inhibition of growth of C4-2 tumors in the bone. Both of the TAX doses inhibited tumor growth, as determined by lower levels of serum PSA in treated versus untreated animals (Fig.…”

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

“…However, when docetaxel was used in combination with dasatinib, the dose resulted in significant decreases in PSA levels beyond those seen with the administration of dasatinib alone. We have previously seen this increased efficacy with the use of other pharmaceuticals in combination with docetaxel over either agent alone (Brubaker et al, 2006;Morgan et al, 2008). In addition, src inhibition has been reported to increase sensitivity of other advanced cancers to several already used chemotherapies and specifically to docetaxel resistance (Yezhelyev et al, 2004;Han et al, 2006).…”

Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

“…Combining bisphosphonates with cytotoxic drugs in vivo has been shown to increase the anticancer effects compared with either drug alone (29,(37)(38)(39). We have shown that clinically relevant doses of doxorubicin (2 mg/kg) combined with a single administration of zoledronic acid (100 μg/kg) reduced intraosseous tumor growth in the B02 model of breast cancer bone metastases (32).…”