Zoledronic Acid Treatment of 5T2MM-Bearing Mice Inhibits the Development of Myeloma Bone Disease: Evidence for Decreased Osteolysis, Tumor Burden and Angiogenesis, and Increased Survival

Croucher, Peter I.; Raeve, Hendrik De; Perry, Mark; Hijzen, Anja; Shipman, C M; Lippitt, Jenny M.; Green, Jonathan; Marck, Eric Van; Camp, Ben Van; Vanderkerken, Karin

doi:10.1359/jbmr.2003.18.3.482

Cited by 249 publications

(194 citation statements)

References 47 publications

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“…It has been postulated that bisphosphonates delay progression of bone metastases via the inhibition of osteoclast-mediated bone resorption, leading to a decrease in the release of tumor-promoting growth factors (22). Our current data show significant reductions in the area of bone exposed to resorbing osteoclasts in treatment groups receiving zoledronic acid.…”

Section: Discussionsupporting

confidence: 58%

“…However, the concentrations of bisphosphonates used in these studies range from 5 to 20 μmol/L for up to 72 hours, compared with the 2 μmol/L circulating plasma concentration detectable in breast cancer patients for 1 to 2 hours following the standard 4-mg infusion of zoledronic acid (17). Antitumor effects of bisphosphonates have also been reported in in vivo model systems that mimic tumorinduced bone disease from a variety of cancer types including breast (18,19), prostate (20), leukemia (21), and multiple myeloma (22). These studies also used high doses and frequent administration of zoledronic acid (from 120 μg/kg 2× per week to 120 μg/kg daily), whereas a clinically relevant dose of zoledronic acid (100 μg/kg 1× per month) was reported not to exert anticancer effects in a model of breast cancer bone metastases (23).…”

Section: Introductionmentioning

confidence: 91%

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Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

Ottewell

Woodward

Lefley

et al. 2009

Molecular Cancer Therapeutics

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Patients with advanced breast cancer frequently develop bone metastases, and at this stage, the disease is considered incurable. Here, we show that a 6-week course of weekly administration of doxorubicin (2 mg/kg), followed 24 hours later by the bisphosphonate zoledronic acid (100 μg/kg), causes substantial inhibition of MDA-MB-436 breast tumor burden in bone of immunocompromised mice, compared with administration of the single agents.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 91%

Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

Ottewell

Woodward

Lefley

et al. 2009

Molecular Cancer Therapeutics

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“…We and others have shown previously that inhibiting bone resorption is also associated with antitumor effects in these experimental models. (43)(44)(45)(46) However, osteoblastic bone formation was not typically examined in these previous studies. This report is one of the first to provide evidence that stimulating osteoblast differentiation and bone formation is also associated with antitumor effects and the reduction of metastases.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Chantry

Heath

Mulivor

et al. 2010

Journal of Bone and Mineral Research

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135

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Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis ( p < .01), promotes bone formation ( p < .01) and increases bone mass in vivo ( p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption ( p < .05) and suppression of bone formation ( p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis ( p < .01), prevents myeloma-induced suppression of bone formation ( p < .05), blocks the development of osteolytic bone lesions ( p < .05), and increases survival ( p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction ( p < .001) and inhibits bone metastases ( p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer. ß

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“…12 Moreover, there is evidence from in vitro studies to suggest that BPs can inhibit invasion 13 and adhesion 14 of breast and prostate cancer cells to bone, and BPs have been shown to have antiangiogenic properties. [15][16][17] N-BPs, such as RIS, act on the mevalonate pathway by specifically inhibiting the enzyme farnesyl diphosphate (FPP) synthase. 18,19 This leads to inhibition of prenylation of target proteins, which mainly include small GTPases such as Ras, Rho, Rac and Rab.…”

mentioning

confidence: 99%

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S‐phase arrest, in human myeloma cells

Roelofs¹,

Hulley²,

Meijer³

et al. 2006

Intl Journal of Cancer

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Bisphosphonates (BPs) are widely used in the treatment of osteolytic bone disease associated with multiple myeloma, and have been demonstrated to exert antitumor effects both in vitro and in vivo. However, the precise molecular mechanisms involved in the direct antitumor effects of BPs in vitro are not known. Nitrogen‐containing BPs, such as risedronate (RIS), act by inhibiting protein prenylation. A phosphonocarboxylate analogue of RIS, 3‐PEHPC, has previously been shown in osteoclasts and macrophages to specifically inhibit prenylation of Rab GTPases. The aim of this study was to identify the molecular targets of RIS and 3‐PEHPC in human myeloma cells and to determine the cellular effects of selective inhibition of Rab prenylation by 3‐PEHPC as compared to nonspecific inhibition of protein prenylation by RIS in human myeloma cells. RIS dose‐dependently inhibited prenylation of both Rap1A and Rab6, whereas 3‐PEHPC only inhibited Rab6 prenylation. Both RIS and 3‐PEHPC dose‐dependently increased apoptosis in human myeloma cells. RIS induced an accumulation of cells in the S‐phase of the cell cycle, associated with inhibition of DNA replication. In contrast, 3‐PEHPC did not cause cell‐cycle arrest. Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell‐cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3‐PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3‐PEHPC. In conclusion, our studies demonstrate that selective inhibition of Rab prenylation induces apoptosis, but not S‐phase arrest, thus identifying distinct molecular pathways that mediate the antimyeloma effect of nitrogen‐containing BPs. © 2006 Wiley‐Liss, Inc.

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Zoledronic Acid Treatment of 5T2MM-Bearing Mice Inhibits the Development of Myeloma Bone Disease: Evidence for Decreased Osteolysis, Tumor Burden and Angiogenesis, and Increased Survival

Cited by 249 publications

References 47 publications

Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S‐phase arrest, in human myeloma cells

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