Pamidronate (P) induces modifications of circulating angiogenetic factors in cancer patients

Santini, Daniele; Vincenzi, Bruno; Cuonzo, G. Di; Battistoni, Fabrizio; Gravasci, M.; Fossati, C; Avvisati, Giuseppe; Denaro, Vincenzo; Campisi, C; Tonini, G.

doi:10.1016/s0959-8049(01)81465-9

Cited by 161 publications

(214 citation statements)

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“…The strong inflammation was accompanied by prominent development of medullary vessels. This argues against the assumption that NBPs, and particularly zoledronic acid, reduce bone angiogenesis [10,11]. Our observation is in keeping with the pronounced boneseeking-isotope uptake, pointing to the persistence of an effective blood supply to the affected site.…”

Section: Discussionsupporting

confidence: 73%

“…It is generally admitted that this adverse effect targets the jaws because they concentrate NBPs owing to their high bone turnover compared with other anatomical sites [8], and bisphosphonate toxicity on osteoclasts [9]. It has also been proposed that NBPs may have an antiangiogenic effect, reducing blood flow and thus inducing bone cell necrosis and apoptosis [10,11]. One alternative explanation is an "outside-in" process in which mucosal damage provides oral bacteria with access to the underlying bone, leading to bone infection and necrosis [12].…”

Section: Introductionmentioning

confidence: 99%

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Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Lesclous

Najm

Carrel

et al. 2009

Bone

194

140

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Osteonecrosis of the jaw (ONJ) can be associated with nitrogen-containing bisphosphonates (NBPs) therapy. Various mechanisms of NBP-associated ONJ have been proposed and there is currently no consensus of the underlying pathogenesis. The detailed medical and dental histories of 30 ONJ patients treated with NBPs for malignant diseases (24) or osteoporosis (6) were analyzed. The necrotic bone was resected and analyzed histologically after demineralization. In 10 patients the perinecrotic bone was also resected and processed without demineralization. Alveolar bone samples from 5 healthy patients were used as controls. In 14 ONJ patients, serial technetium-99m-methylene diphosphonate scintigraphic scans were also available and confronted to the other data. Strong radionuclide uptake was detected in some patients several months before clinical diagnosis of ONJ. The medullary spaces of the necrotic bone were filled with bacterial aggregates. In the perinecrotic bone, the bacteria-free bone marrow characteristically showed an inflammatory reaction. The number of medullary inflammatory cells taken as an index of inflammation allowed us to discriminate two inflammation grades in the ONJ samples. Low-grade inflammation, characterized by marrow fibrosis and low inflammatory cells infiltration, increased numbers of TRAP + monoand multineacleated cells was seen in patients with bone exposure b 2 cm 2 . High-grade inflammation, associated with larger lesions, showed amounts of tartrate-resistant acid phosphatase + /calcitonin receptor − mono-and multinucleated cells, osteocyte apoptosis, hypervascularization and high inflammatory cell infiltration. The clinical extent of ONJ was statistically linked to the numbers of inflammatory cell. Taken together these data suggest that bone necrosis precedes clinical onset and is an inflammation-associated process. We hypothesize that from an initial focus, bone damage spreads centrifugally, both deeper into the jaw and towards the mucosa before the oral bone exposure and the clinical diagnosis of ONJ.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Lesclous

Najm

Carrel

et al. 2009

Bone

194

140

View full text Add to dashboard Cite

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“…16,17 Results from the analysis of SRE outcomes confirm findings from other metastatic prostate cancer studies, and confirm the benefits of ZA in reducing skeletal morbidity. Consistent with the evidence of ZA anticancer activities from recent breast cancer studies, 19,[24][25][26] we found evidence of prolonged overall survival with ZA among patients with prostate cancer. While earlier studies of ZA in prostate cancer did not show significant overall survival benefit with this therapy, the present study found that timely ZA treatment significantly reduced mortality risk during the first 6 months after diagnosis of bone metastasis.…”

Section: Discussionsupporting

confidence: 90%

The benefits of timely intervention with zoledronic acid in patients with metastatic prostate cancer to bones: a retrospective study of the US Veterans Affairs population

Velde

Guo

et al. 2010

Prostate Cancer Prostatic Dis

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To examine the effect of timely zoledronic acid (ZA) treatment on clinical outcomes and health care utilization in patients with bone-metastatic prostate cancer. Patients with prostate cancer and bone metastasis were identified in a Veterans Affairs database (01/2002-09/2009). Eligible patients had no documented skeletal-related events (SREs) before the index date (that is, the first bone metastasis diagnosis date). Patients who received early ZA treatment, defined as having a ZA infusion after the index date and before any recorded SREs, were matched 1:1 on propensity score to patients not treated with bisphosphonates (BPs). Risks of SREs, hospitalization and death during the 6-month post-index period were compared between matched cohorts using Kaplan-Meier analyses. Baseline characteristics were well balanced between the matched cohorts (n ¼ 73 per group). 6-month SRE-free survival and hospitalization-free survival were higher in patients receiving timely ZA than patients without BP treatment (91.7 versus 71.5%, Po0.01; 80.5 versus 66.3%, P ¼ 0.05, respectively). 6-month mortality risk was significantly lower in patients treated with ZA versus those without BP treatment (4.3 versus 13.8%, P ¼ 0.04). Timely ZA intervention in bone-metastatic prostate cancer patients was associated with significant reductions in 6-month risks of SREs, hospitalization and mortality, as compared with no BP treatment.

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“…These include inhibition of tumor cell growth and induction of cancer cell apoptosis, 8 -12 inhibition of tumor cell adhesion and invasion [13][14][15] and, more recently, antiangiogenic activity. 16,17 In preclinical testing, zoledronic acid has been shown to be the most potent inhibitor of bone resorption compared to other bisphosphonates 18 and this potency is also reflected in the various antitumor activities investigated to date. Furthermore, zoledronic acid has shown synergistic induction of cancer cell apoptosis in vitro when combined with a variety of agents, e.g., with imatinib mesylate in leukemia cells 19 or in lung cancer cells, 20 with gemcitabine in prostate cancer cells, 21 with paclitaxel or tamoxifen 22,23 or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 24 in breast cancer cells and with dexamethasone in myeloma cells.…”

mentioning

confidence: 99%

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Neville-Webbe

Rostami‐Hodjegan

Evans

et al. 2004

Intl Journal of Cancer

146

104

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We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence-and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.Key words: breast cancer; apoptosis; zoledronic acid; doxorubicin; synergistic interaction Zoledronic acid is a potent third-generation nitrogen-containing bisphosphonate and is the only bisphosphonate licensed to treat bone metastases from a variety of solid tumors and in multiple myeloma. In clinical practice, an increasing number of breast and prostate cancer patients are receiving zoledronic acid at earlier stages of their treatment in order to manage their metastatic bone disease.Zoledronic acid inhibits osteoclastic bone resorption, which occurs at an accelerated pace due to the presence of tumor cells in the bone microenvironment. 1 Nitrogen-containing bisphosphonates affect osteoclast action by inhibition of enzymes of the mevalonate pathway. 2 Target enzymes include farnesyl pyrophosphate synthase 3,4 and/or geranylgeranylpyrophosphate synthase, 5 leading to a lack of formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These isoprenoids are requisite for posttranslation lipid modification (i.e., farnesylation and geranylgeranylation) of signaling GTPases, such as Ras, Rho and Rac. 6 As these control a variety of important osteoclast cell functions, their loss ultimately leads to osteoclast apoptosis through caspase-3 enzyme activation. 7 In addition to their inhibitory effect on osteocl...

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Pamidronate (P) induces modifications of circulating angiogenetic factors in cancer patients

Cited by 161 publications

References 0 publications

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

The benefits of timely intervention with zoledronic acid in patients with metastatic prostate cancer to bones: a retrospective study of the US Veterans Affairs population

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

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