A promising approach for treatment of tumor-induced bone diseases: utilizing bisphosphonate derivatives of nucleoside antimetabolites.
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-MIP1alpha multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04 microg/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 microg/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-MIP1alpha cells, 0.04 and 4.0 microg/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< or =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.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55906, USA. reinholz.monica@mayo.edu
Monica M
MM
Reinholz
Shawn P
SP
Zinnen
Amylou C
AC
Dueck
David
D
Dingli
Gregory G
GG
Reinholz
Leslie A
LA
Jonart
Kathleen A
KA
Kitzmann
Amy K
AK
Bruzek
Vivian
V
Negron
Abdalla K
AK
Abdalla
Bonnie K
BK
Arendt
Anthony J
AJ
Croatt
Luis
L
Sanchez-Perez
David P
DP
Sebesta
Harri
H
Lönnberg
Toshiyuki
T
Yoneda
Karl A
KA
Nath
Diane F
DF
Jelinek
Stephen J
SJ
Russell
James N
JN
Ingle
Thomas C
TC
Spelsberg
Henry B F Hal
HB
Dixon
Alexander
A
Karpeisky
Wilma L
WL
Lingle
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects; D001847:Bone Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000150:complications*; D009705:Nucleosides / Q000494:pharmacology / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000963:Antimetabolites; D004164:Diphosphonates; D009705:Nucleosides