Reduction in New Metastases in Breast Cancer with Adjuvant Clodronate Treatment

Diel, Ingo J.; Solomayer, Erich‐Franz; Costa, Serban Dan; Gollan, Christina; Goerner, R.; Wallwiener, D.; Kaufmann, M.; Bastert, G.

doi:10.1056/nejm199808063390601

Cited by 751 publications

(419 citation statements)

References 26 publications

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“…This observation constitutes an important addition to the mechanistic understanding of how BPs, given in adjuvant setting, could prevent the development of bone metastases as shown by two clinical trials (Diel et al, 1998;Powles et al, 2002). Moreover, we attempted to elucidate whether this effect of ZOL could be explained by the inhibition of the MVA pathway, and more particularly by RhoA inactivation.…”

Section: Discussionmentioning

confidence: 95%

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New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Denoyelle¹,

Li²,

Jp³

et al. 2003

Br J Cancer

147

110

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Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and its use in reducing osteoporosis and cancer-induced osteolysis is increasing. Recent findings indicated that ZOL has a direct effect on cancer cells. In this study, the effect of ZOL was examined on the aggressive MDA-MB-231 breast cancer cell line. ZOL induces an important inhibition of cell invasion at low concentrations (1 mM). This is not explained by modifications of proteases involved in cell invasiveness (matrix metalloproteinases and urokinase-type plasminogen activator), but by a disorganisation of actin cytoskeleton due to RhoA inhibition related to its defective prenylation as it was reversed by geranylgeraniol (GGOH) and mimicked by the Rho selective inhibitor C3 exoenzyme. In addition, ZOL inhibits the chemotactic effect induced by stromal cell-derived factor 1(SDF-1), a chemokine greatly involved in cancer metastasis to bone. This effect is related to both reduction of cell motility induced by RhoA inhibition and to a decreased expression of CXCR-4, the SDF-1 receptor. Finally, ZOL reduces Cox-2 expression and, consequently, the secretion of prostaglandins E2 (PGE2) in a RhoAindependent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclastmediated bone resorption. In summary, new insights in the mechanism of ZOL action on aggressive breast cancer cells are demonstrated and could explain its beneficial action in both the reduction of osteolysis and prevention of metastasis.

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Section: Discussionmentioning

confidence: 95%

“…Two clinical trials of patients with breast cancer demonstrated that BPs, given in adjuvant setting, reduce the incidence of skeletal metastasis with a consequent improvement in survival (Diel et al, 1998;Powles et al, 2002). However, other authors reported opposite results (Saarto et al, 2001).…”

mentioning

confidence: 99%

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Denoyelle¹,

Li²,

Jp³

et al. 2003

Br J Cancer

147

110

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“…In recent years bisphosphonates have become important in the management of cancer-induced bone disease and are now well established in the management of patients with multiple myeloma and bone metastases secondary to breast cancer (Paterson et al, 1993;Berenson et al, 1996;Hortobagyi et al, 1996;Diel et al, 1998;McCloskey et al, 1998;Theriault et al, 1999). Randomized controlled trials in patients with breast cancer have demonstrated that clodronate and pamidronate reduce skeletal morbidity and improve quality of life (Paterson et al, 1993;Hortobagyi et al, 1996;Kanis et al, 1996).…”

mentioning

confidence: 99%

“…Randomized controlled trials in patients with breast cancer have demonstrated that clodronate and pamidronate reduce skeletal morbidity and improve quality of life (Paterson et al, 1993;Hortobagyi et al, 1996;Kanis et al, 1996). Furthermore, in the adjuvant situation, studies with oral clodronate suggest that the use of bisphosphonates in combination with chemotherapy or endocrine therapy may delay first recurrence in bone (Diel et al, 1998). In addition, Diel et al have shown that treatment with oral clodronate may be associated with reduced rates of visceral metastases and improved survival compared with those receiving standard antineoplastic therapy alone (Diel et al, 1998).…”

mentioning

confidence: 99%

“…Furthermore, in the adjuvant situation, studies with oral clodronate suggest that the use of bisphosphonates in combination with chemotherapy or endocrine therapy may delay first recurrence in bone (Diel et al, 1998). In addition, Diel et al have shown that treatment with oral clodronate may be associated with reduced rates of visceral metastases and improved survival compared with those receiving standard antineoplastic therapy alone (Diel et al, 1998). However, the role of bisphosphonates in the adjuvant setting remains to be clarified as Saarto et al reported an increase in the frequency of bone and visceral metastases with poorer survival in clodronate treated patients when compared with control (Saarto et al, 2000).…”

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confidence: 99%

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The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel

et al. 2001

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SummaryBisphosphonates are well established in the management of breast-cancer-induced bone disease. Recent studies have suggested that these compounds are effective in preventing the development of bone metastases. However, it is unclear whether this reflects an indirect effect via an inhibition of bone resorption or a direct anti-tumour effect. The breast cancer cell lines, MCF-7 and MDA-MB-231 cells were treated with increasing concentrations of the bisphosphonate, zoledronic acid, for varying time periods, in the presence or absence of paclitaxel. The effects of zoledronic acid were determined by assessing cell number and rate of apoptosis by evaluating changes in nuclear morphology and using a fluorescence nick translation assay. Zoledronic acid caused a dose-and time-dependent decrease in cell number (P < 0.001) and a concomitant increase in tumour cell apoptosis (P < 0.005). Short-term exposure to zoledronic acid was sufficient to cause a significant reduction in cell number and increase in apoptosis (P < 0.05). These effects could be prevented by incubation with geranyl geraniol, suggesting that zoledronic acid-induced apoptosis is mediated by inhibiting the mevalonate pathway. Treatment with zoledronic acid and clinically achievable concentrations of paclitaxel resulted in a 4-5-fold increase in tumour cell apoptosis (P < 0.02). Isobologram analysis revealed synergistic effects on tumour cell number and apoptosis when zoledronic acid and paclitaxel were combined. Short-term treatment with zoledronic acid, which closely resembles the clinical setting, has a clear anti-tumour effect on breast cancer cells. Importantly, the commonly used antineoplastic agent, paclitaxel, potentiates the anti-tumour effects of zoledronic acid. These data suggest that, in addition to inhibiting bone resorption, zoledronic acid has a direct anti-tumour activity on breast cancer cells in vitro.

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Vertebral Fractures and Mortality in Older Women

Kado

Browner²,

Palermo³

et al. 1999

Arch Intern Med

925

171

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Reduction in New Metastases in Breast Cancer with Adjuvant Clodronate Treatment

Abstract: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases.

Cited by 751 publications

References 26 publications

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel

Vertebral Fractures and Mortality in Older Women

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