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

Monica M. Reinholz, Shawn P. Zinnen, Amylou C. Dueck, David Dingli, Gregory G. Reinholz, Leslie A. Jonart, Kathleen A. Kitzmann, Amy K. Bruzek, Vivian Negron, Abdalla K. Abdalla, Bonnie K. Arendt, Anthony J. Croatt, Luis Sanchez-Perez, David P. Sebesta, Harri Lönnberg, Toshiyuki Yoneda, Karl A. Nath, Diane F. Jelinek, Stephen J. Russell, James N. IngleThomas C. Spelsberg, Henry B.F. Dixon, Alexander Karpeisky, Wilma L. Lingle

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)12-22
Number of pages11
JournalBone
Volume47
Issue number1
DOIs
StatePublished - Jul 2010

Bibliographical note

Funding Information:
Dr. Monica Reinholz received research funding for supplies and animals from MBC Pharma to supplement a portion of the in vivo efficacy studies that was not supported by the NIH grants. Dr. Reinholz, her spouse, or any of her dependents have no personal financial interest (such as company stocks or shares or equity) in MBC Pharma. Drs. Zinnen, Sebesta, and Karpeisky were employees of MBC Pharma at the time the work was performed. All other co-authors have no personal financial interest in MBC Pharma or conflicts of interest.

Funding Information:
This work was supported by United States National Institutes of Health grants, P01CA062242 (PI: DF Jelinek), 1R41CA097577 and 1R41CA105583 (PI: MM Reinholz), MBC Pharma research grants RRF31J and 3X1127 (PI: MM Reinholz), and MBC Pharma Inc . We thank Drs. Nelly Paduykova, Sergei Mikhailov (Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia), and Dr. Andrei Guzaev (AM Chemicals, Oceanside CA) for the synthesis of the conjugates. We thank Mr. Darren Riehle for making digital images of the bone histology and Dr. Kara Lukasiewicz for critical review of this manuscript.

Keywords

  • Bisphosphonates
  • Bone cancer
  • Chemotherapeutics
  • Drug conjugation
  • Targeting

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