A promising approach for treatment of tumor-induced bone diseases: Utilizing bisphosphonate derivatives of nucleoside antimetabolites

Abstract: Despite palliative treatments, tumor-induced bone disease (TIBD) remains highly debilitating for many cancer patients and progression typically results in death within two years. Therefore, more effective therapies with enhanced anti-resorptive and cytotoxic characteristics are needed. We developed bisphosphonate-chemotherapeutic conjugates designed to bind bone and hydrolyze, releasing both compounds, thereby targeting both osteoclasts and tumor cells. This study examined the effects of our lead compound, MBC-11 (the anhydride formed between arabinocytidine (AraC)-5′-phosphate and etidronate), on bone tumor burden, bone volume, femur bone mineral density (BMD), and overall survival using two distinct mouse models of TIBD, the 4T1/luc breast cancer and the KAS-6/1-MIP1α multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04μg/day; s.c.) reduced the incidence of bone metastases to 40% (4/10), compared to 90% (9/10; p =0.057) and 100% (5/5; p =0.04) of PBS- or similarly-dosed, zoledronate-treated mice, respectively. MBC-11 also significantly decreased bone tumor burden compared to PBS- or zoledronate-treated mice (p =0.021, p =0.017, respectively). MBC-11 and zoledronate (0.04μg/day) significantly increased bone volume by two- and four-fold, respectively, compared to PBS-treated mice (p =0.005, p <0.001, respectively). In mice systemically injected with human multiple myeloma KAS-6/1-MIP1α cells, 0.04 and 4.0μg/day MBC-11 improved femur BMD by 13% and 16%, respectively, compared to PBS (p =0.025, p =0.017, respectively) at 10weeks post-tumor cell injection and increased mean survival to 95days compared to 77days in mice treated with PBS (p =0.047). Similar doses of zoledronate also improved femur BMD (p ≤0.01 vs PBS) and increased mean survival to 86days, but this was not significantly different than in PBS-treated mice (p =0.53). These results demonstrate that MBC-11 decreases bone tumor burden, maintains bone structure, and may increase overall survival, warranting further investigation as a treatment for TIBD. [Copyright &y& Elsevier]