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

Monica M. Reinholz, Shawn P. Zinnen, Amylou Dueck, David M 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 journalArticle

22 Citations (Scopus)

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

Fingerprint

Antimetabolites
Bone Diseases
Diphosphonates
zoledronic acid
Nucleosides
Bone and Bones
Neoplasms
Tumor Burden
Bone Density
Femur
Therapeutics
Survival
Multiple Myeloma
Etidronic Acid
Anhydrides
Osteoclasts
Palliative Care
Breast
Phosphates
Breast Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

A promising approach for treatment of tumor-induced bone diseases : Utilizing bisphosphonate derivatives of nucleoside antimetabolites. / Reinholz, Monica M.; Zinnen, Shawn P.; Dueck, Amylou; Dingli, David M; Reinholz, Gregory G.; Jonart, Leslie A.; Kitzmann, Kathleen A.; Bruzek, Amy K.; Negron, Vivian; Abdalla, Abdalla K.; Arendt, Bonnie K.; Croatt, Anthony J.; Sanchez-Perez, Luis; Sebesta, David P.; Lönnberg, Harri; Yoneda, Toshiyuki; Nath, Karl A; Jelinek, Diane F; Russell, Stephen J; Ingle, James N.; Spelsberg, Thomas C.; Dixon, Henry B F; Karpeisky, Alexander; Lingle, Wilma L.

In: Bone, Vol. 47, No. 1, 07.2010, p. 12-22.

Research output: Contribution to journalArticle

Reinholz, MM, Zinnen, SP, Dueck, A, Dingli, DM, Reinholz, GG, Jonart, LA, Kitzmann, KA, Bruzek, AK, Negron, V, Abdalla, AK, Arendt, BK, Croatt, AJ, Sanchez-Perez, L, Sebesta, DP, Lönnberg, H, Yoneda, T, Nath, KA, Jelinek, DF, Russell, SJ, Ingle, JN, Spelsberg, TC, Dixon, HBF, Karpeisky, A & Lingle, WL 2010, 'A promising approach for treatment of tumor-induced bone diseases: Utilizing bisphosphonate derivatives of nucleoside antimetabolites', Bone, vol. 47, no. 1, pp. 12-22. https://doi.org/10.1016/j.bone.2010.03.006
Reinholz, Monica M. ; Zinnen, Shawn P. ; Dueck, Amylou ; Dingli, David M ; Reinholz, Gregory G. ; Jonart, Leslie A. ; Kitzmann, Kathleen A. ; Bruzek, Amy K. ; Negron, Vivian ; Abdalla, Abdalla K. ; Arendt, Bonnie K. ; Croatt, Anthony J. ; Sanchez-Perez, Luis ; Sebesta, David P. ; Lönnberg, Harri ; Yoneda, Toshiyuki ; Nath, Karl A ; Jelinek, Diane F ; Russell, Stephen J ; Ingle, James N. ; Spelsberg, Thomas C. ; Dixon, Henry B F ; Karpeisky, Alexander ; Lingle, Wilma L. / A promising approach for treatment of tumor-induced bone diseases : Utilizing bisphosphonate derivatives of nucleoside antimetabolites. In: Bone. 2010 ; Vol. 47, No. 1. pp. 12-22.
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AU - Reinholz, Monica M.

AU - Zinnen, Shawn P.

AU - Dueck, Amylou

AU - Dingli, David M

AU - Reinholz, Gregory G.

AU - Jonart, Leslie A.

AU - Kitzmann, Kathleen A.

AU - Bruzek, Amy K.

AU - Negron, Vivian

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AU - Croatt, Anthony J.

AU - Sanchez-Perez, Luis

AU - Sebesta, David P.

AU - Lönnberg, Harri

AU - Yoneda, Toshiyuki

AU - Nath, Karl A

AU - Jelinek, Diane F

AU - Russell, Stephen J

AU - Ingle, James N.

AU - Spelsberg, Thomas C.

AU - Dixon, Henry B F

AU - Karpeisky, Alexander

AU - Lingle, Wilma L.

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N2 - 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.

AB - 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.

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