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

: Reinholz MM, Zinnen SP, Dueck AC, Dingli D, Reinholz GG, Jonart LA, Kitzmann KA, Bruzek AK, Negron V, Abdalla AK, Arendt BK, Croatt AJ, Sanchez-Perez L, Sebesta DP, Lonnberg H, Yoneda T, Nath KA, Jelinek DF, Russell SJ, Ingle JN, Spelsberg TC, Dixon HBF, Karpeisky A, Lingle WL

Publisher: ELSEVIER SCIENCE INC

: 2010

: BONE

: 1

: 47

: 1

: 12

: 22

: 11

: 8756-3282

DOI: https://doi.org/10.1016/j.bone.2010.03.006

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-MIP1 alpha multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04 mu g/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 (0.04 mu g/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-MIP1 alpha cells, 0.04 and 4.0 mu g/day MBC-11 improved femur BMD by 13% and 16%, respectively, compared to PBS (p = 0.025,p = 0.017, respectively) at 10 weeks post-tumor cell injection and increased mean survival to 95 days compared to 77 days 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 86 days, 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. (C) 2010 Elsevier Inc. All rights reserved.

Chemical sciences