Nitrogen-containing bisphosphonates inhibit cell cycle progression in human melanoma cells

Cutaneous melanoma is one of the highly malignant human tumours, due to its tendency to generate early metastases and its resistance to classical chemotherapy. We recently demonstrated that pamidronate, a nitrogen-containing bisphosphonate, has an antiproliferative and proapoptotic effect on different melanoma cell lines. In the present study, we compared the in vitro effects of three different bisphosphonates on human melanoma cell lines and we demonstrated that the two nitrogen-containing bisphosphonates pamidronate and zoledronate inhibited the proliferation of melanoma cells and induced apoptosis in a dose- and time-dependent manner. Moreover, cell cycle progression was altered, the two compounds causing accumulation of the cells in the S phase of the cycle. In contrast, the nonaminobisphosphonate clodronate had no effect on melanoma cells. These findings suggest a direct antitumoural effect of bisphosphonates on melanoma cells in vitro and further support the hypothesis of different intracellular mechanisms of action for nitrogen-containing and nonaminobisphosphonates. Our data indicate that nitrogen-containing bisphosphonates may be a useful novel therapeutic class for treatment and/or prevention of melanoma metastases.     

Bisphosphonates induce apoptosis in human breast cancer cell lines

Breast cancer has a prodigious capacity to metastasize to bone. In women with advanced breast cancer and bone metastases, bisphosphonates reduce the incidence of hypercalcaemia and skeletal morbidity. Recent clinical findings suggest that some bisphosphonates reduce the tumour burden in bone with a consequent increase in survival, raising the possibility that bisphosphonates may have a direct effect on breast cancer cells. We have investigated the in vitro effects of bisphosphonates zoledronate, pamidronate, clodronate and EB 1053 on growth, viability and induction of apoptosis in three human breast cancer cell lines (MDA-MB-231, Hs 578T and MCF-7). Cell growth was monitored by crystal violet dye assay, and cell viability was quantitated by MTS dye reduction. Induction of apoptosis was determined by identification of morphological features of apoptosis using time-lapse videomicroscopy, identifying morphological changes in nucleis using Hoechst staining, quantitation of DNA fragmentation, level of expression of bcl-2 and bax proteins and identification of the proteolytic cleavage of Poly (ADP)-ribose polymerase (PARP). All four bisphosphonates significantly reduced cell viability in all three cell lines. Zoledronate was the most potent bisphosphonate with IC50 values of 15, 20 and 3 microM respectively in MDA-MB-231, MCF-7 and Hs 578T cells. Corresponding values for pamidronate were 40, 35 and 25 microM, whereas clodronate and EB 1053 were more than two orders of magnitude less potent. An increase in the proportion of cells having morphological features characteristic of apoptosis, characteristic apoptotic changes in the nucleus, time-dependent increase in the percentage of fragmented chromosomal DNA, down-regulation in bcl-2 protein and proteolytic cleavage of PARP, all indicate that bisphosphonates have direct anti-tumour effects on human breast cancer cells.     

Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts

Bisphosphonates are widely used clinically to treat bone diseases in which bone resorption is in excess. However, the mechanism of bisphosphonate action on bone is not fully understood. Studies of direct action of bisphosphonates on bone have been limited mainly to their effects on bone-resorbing osteoclast cells, with implications that some activity may be mediated indirectly through paracrine factors produced by the bone-forming osteoblast cells. Little is known about the direct effects of bisphosphonates on osteoblasts. In this report, the direct actions of several bisphosphonates on cell proliferation, gene expression, and bone formation by cultured human fetal osteoblasts were examined. Osteoblast cell proliferation was decreased, and cytodifferentiation was increased in a dose-dependent manner in cultures treated with the bisphosphonate pamidronate. In addition, pamidronate treatment increased total cellular protein, alkaline phosphatase activity, and type I collagen secretion in osteoblasts. Consistent with the above-mentioned findings, the rate of bone formation was also increased in osteoblasts cultured with pamidronate. The actions of two other bisphosphonates, the weak-acting etidronate and the potent new analogue zoledronate, were also compared with the action of pamidronate on proliferation of immortalized human fetal osteoblast (hFOB) cells and rate of bone formation. Pamidronate and zoledronate decreased hFOB cell proliferation with equal potency, whereas etidronate decreased proliferation only at much higher concentrations. Studies comparing EDTA and etidronate indicate that etidronate may act indirectly on the hFOB cells by reducing free divalent ion concentrations, whereas pamidronate and zoledronate appear to act on the hFOB cells by a direct action. Both pamidronate and zoledronate increase hFOB cell bone formation, whereas no increase is observed with etidronate and EDTA. Taken together, these observations strongly suggest that treatment with pamidronate or zoledronate enhances the differentiation and bone-forming activities of osteoblasts.     

Bisphosphonates: biological response modifiers in breast cancer

Bone recurrence constitutes one third of initial sites of relapse and one half of distant sites of relapse at 10 years from diagnosis of breast cancer. Bone pain, fracture (including vertebral fracture resulting from increased bone resorption following chemotherapy-induced menopause), and hypercalcemia are components of skeletal morbidity. The pathophysiology of malignant osteopathy occurs because of the secretion of substances (such as parathyroid hormone-related peptide), by the malignant cell, which stimulate osteoclast function; this in turn feeds further growth, which causes a vicious cycle. Interruption of this cycle by bisphosphonates may inhibit the growth of malignant cells. Bisphosphonates are drugs that inhibit bone turnover by decreasing bone resorption. Side effects of bisphosphonates include upper gastrointestinal symptoms (in oral nitrogen-containing bisphosphonates) and diarrhea (in oral non-nitrogen-containing bisphosphonates) and an acute phase-like reaction with intravenous (I.V.) pamidronate. Bisphosphonates have different molecular mechanisms of action: Nitrogen-containing bisphosphonates (eg, pamidronate and alendronate) inhibit the mevalonate-signaling pathway while the non-nitrogen-containing drugs (eg, clodronate) incorporate into adenosine triphosphate analogues. There is in vitro evidence that these drugs also possess anticancer properties. In hypercalcemia patients, treatment with pamidronate and zoledronate produce prompt and efficient normocalcemia. Intravenous pamidronate and zoledronate, oral clodronate, and ibandronate reduce skeletal complications in patients with bone metastases; I.V. pamidronate and clodronate are useful for bone pain relief. Three adjuvant bisphosphonate trials are discussed herein: 2 small open-label studies giving conflicting results and a large placebo-controlled trial of oral clodronate. This latter trial shows a reduction in the incidence of skeletal metastases (while the patients are on therapy) and an improved survival at 5 years.     

Anti-tumour activity of bisphosphonates in human myeloma cells

Multiple myeloma is a haematological malignancy characterized by an expansion of malignant plasma cells within the bone marrow and is frequently associated with bone disease involving the development of osteolytic bone lesions, pathological fractures, osteoporosis and hypercalcaemia. A class of anti-resorptive drugs known as bisphosphonates have been in use to treat osteoclast-mediated bone diseases for the past 3 decades, and are currently proving effective in the treatment of the bone disease associated with multiple myeloma. Recent studies have suggested that bisphosphonate treatment may also result in an improvement in survival in some patients with multiple myeloma. These effects on survival may reflect an indirect effect of the bisphosphonates on tumour growth, via inhibition of osteoclast activity and hence a reduction in the release of tumour growth factors. However, it is also possible that bisphosphonates may have a direct effect on myeloma cells. In support of this we have demonstrated that bisphosphonates can decrease cell proliferation and induce apoptosis in human myeloma cells in vitro, and this review discusses the possibility that bisphosphonates may have not only an anti-resorptive action, but may also have a direct anti-tumour activity.     

Bone complications in multiple myeloma

Multiple myeloma is the malignant proliferation of plasma cells involving more than 10% of the bone marrow. The bone complications associated with multiple myeloma include bone pain, pathologic fractures, hypercalcemia of malignancy and cord compressions. The principal pathophysiology of bone disease in multiple myeloma is a shift in the balance of bone remodeling toward bone resorption. In recent years, bisphosphonates have become an important treatment for the bone complications of multiple myeloma. Potent inhibitors of osteoclast activity, bisphosphonates interfere with biochemical pathways and induce osteoclast apoptosis. Bisphosphonates also antagonize osteoclastogenesis and promote differentiation of osteoblasts, as well as inhibiting other aspects of osteoclast homeostasis and metabolism. Several studies have evaluated treatment with bisphosphonates in patients with multiple myeloma, and have demonstrated the efficacy of clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ; www.bonefos.com), pamidronate (Aredia; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.pamidronate.com) and zoledronic acid (Zometa; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.us.zometa.com) in reduction of pain, reduction of SREs and survival. Moreover, recent data suggest direct and indirect antimyeloma activity of pamidronate and zoledronic acid.     

Bisphosphonate treatment inhibits the growth of prostate cancer cells

The presence of skeletal metastases in patients suffering from cancer leads to a variety of clinical complications. Bisphosphonates are a class of drugs with a potent bone resorption inhibition activity that have found increasing utility in treating and managing patients with metastatic bone disease. Several clinical trials have demonstrated that bisphosphonates have clinical value in the treatment and management of skeletal metastases derived from advanced prostate cancer. Currently, the mechanism(s) through which bisphosphonates exert their activity is only beginning to be understood. We have studied the effects of bisphosphonate treatment on the growth of prostate cancer cell lines in vitro. Treatment of PC3, DU145, and LNCaP cells with pamidronate or zoledronate significantly reduced the growth of all three cell lines. Using flow cytometry, pamidronate treatment (100 microM) was shown to induce significant amounts of cell death in all three cell lines studied. In contrast, treatment with zoledronate (100 microM) did not induce cell death, instead exerting dramatic effects on cell proliferation, as evidenced by a major increase in cells present in the G0-G1 and S phase. Although both drugs reduced prostate cancer cell growth in the presence of serum, zoledronate was more potent under these conditions, disrupting growth at doses as low as 25 microM in the presence of 5% fetal bovine serum. These results raise the intriguing possibility that the observed clinical utility of bisphosphonates in managing skeletal metastases may in part derive from direct inhibition of prostate cancer cell growth in the bone microenvironment.     

Management of Metastatic Bone Disease and Hypercalcemia of Malignancy

Thirty years of research have established bisphosphonates as the most effective agents for the inhibition of osteoclast-mediated bone resorption, and they play an important role in the management of malignant bone disease. Bisphosphonates have been systematically improved through chemical engineering, and the newest nitrogen-containing compounds, including zoledronic acid and ibandronate, are 1000-fold more potent than first-generation compounds. Consequently, they can be administered at low molar doses via short intravenous infusions without compromising renal safety. Bisphosphonates have a variety of metabolic effects on osteoclasts. Nitrogen-containing bisphosphonates inhibit protein prenylation via the mevalonate pathway, thereby inhibiting osteoclast activation and inducing apoptosis. Preclinical studies suggest that bisphosphonates also have direct and indirect antitumor activity. In animal models, bisphosphonates reduced skeletal tumor burden and bone metastases. Currently, intravenous bisphosphonates are the standard therapy for hypercalcemia of malignancy, and they have become an integral part of the treatment of bone metastases in conjunction with standard antineoplastic agents. Intravenous bisphosphonates quickly normalize serum calcium, reduce skeletal complications, and palliate bone pain in patients with bone metastases. Intravenous pamidronate (90mg via 2-hour infusion every 3–4 weeks) has, until recently, been the international standard for the treatment of osteolytic bone lesions from breast cancer or multiple myeloma. However, 4mg zoledronic acid (via 15-minute infusion) is quickly becoming the new standard based on evidence that it is as safe and effective as 90mg pamidronate in patients with breast cancer and multiple myeloma and significantly more effective for hypercalcemia of malignancy. Consequently, the American Society of Clinical Oncology guidelines for breast cancer and multiple myeloma recommend pamidronate or zoledronic acid for patients with radiographic evidence of osteolytic bone destruction. Moreover, 4mg zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit in patients with other solid tumors, including lung cancer, and prostate cancer patients with primarily osteoblastic bone metastases. Bisphosphonates also may have activity in the adjuvant setting to prevent or delay the development of bone metastases. Studies with oral clodronate in early breast cancer have provided clinical evidence that bone metastases can be inhibited, and the studies are ongoing with more potent bisphosphonates. Bisphosphonates have also been shown to prevent cancer treatment-induced bone loss. These and other studies continue to redefine the role of bisphosphonates in the treatment of malignant bone disease and the management of bone health in cancer patients.     

Bisphosphonates suppress insulin‐like growth factor 1‐induced angiogenesis via the HIF‐1α/VEGF signaling pathways in human breast cancer cells

Adjunctive chemotherapy with bisphosphonates has been reported to delay bone metastasis and improve overall survival in breast cancer. Aside from its antiresorptive effect, bisphosphonates exhibit antitumor activities, in vitro and in vivo, via several mechanisms, including antiangiogenesis. In this study, we investigated the potential molecular mechanisms underlying the antiangiogenic effect of non–nitrogen‐containing and nitrogen‐containing bisphosphonates, clodronate and pamidronate, respectively, in insulin‐like growth factor (IGF)‐1 responsive human breast cancer cells. We tested whether bisphosphonates had any effects on hypoxia‐inducible factor (HIF)‐1α/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis, and our results showed that both pamidronate and clodronate significantly suppressed IGF‐1‐induced HIF‐1α protein accumulation and VEGF expression in MCF‐7 cells. Mechanistically, we found that either pamidronate or clodronate did not affect mRNA expression of HIF‐1α, but they apparently promoted the degradation of IGF‐1‐induced HIF‐1α protein. Meanwhile, we found that the presence of pamidronate and clodronate led to a dose‐dependent decease in the newly‐synthesized HIF‐1α protein induced by IGF‐1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting the inhibition of protein synthesis. In addition, our results indicated that the inhibitory effects of bisphosphonates on the HIF‐1α/VEGF axis are associated with the inhibition of the phosphoinositide 3‐kinase/AKT/mammalian target of rapamycin signaling pathways. Consistently, we demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF‐1‐stimulated MCF‐7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in the inhibition of tumor angiogenesis in breast cancer cells.     

How Do Bisphosphonates Inhibit Bone Metastasis In Vivo?

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and have demonstrated clinical utility in the treatment of patients with osteolytic bone metastases. They also exhibit direct antitumor activity in vitro and can reduce skeletal tumor burden and inhibit the formation of bone metastases in vivo. However, whether such effects are caused by a direct action of bisphosphonates on tumor cells or indirectly through inhibition of bone resorption remains unclear. To address this question, we used here a structural analog of the bisphosphonate risedronate, NE-58051, which has a bone mineral affinity similar to that of risedronate, but a 3000-fold lower bone antiresorptive activity. In vitro, risedronate and NE-58051 inhibited proliferation of breast cancer and melanoma cell lines. In vivo, risedronate and NE-58051 did not inhibit the growth of subcutaneous B02 breast tumor xenografts or the formation of B16F10 melanoma lung metastasis. In contrast to NE-58051, risedronate did inhibit B02 breast cancer bone metastasis formation by reducing both bone destruction and skeletal tumor burden, indicating that the antitumor effect of bisphosphonates is achieved mainly through inhibition of osteoclast-mediated bone resorption.     

Alendronate inhibits proliferation and invasion of human epidermoid carcinoma cells in vitro

There is increasing evidence that bisphosphonates have direct antitumor effects in vivo in addition to their therapeutic antiresorptive properties. Bisphosphonates inhibit proliferation and induce apoptosis of many cancer cell lines. They also exhibit anti-invasive properties in vitro and in vivo. We have previously shown that a novel non-nitrogen-containing bisphosphonate inhibited tumor growth of A431 human epidermoid carcinoma cells. In the present study, we investigated the antitumor properties of three nitrogen-containing bisphosphonates on A431 cells in vitro. We first compared the antiproliferative effects of pamidronate, alendronate and neridronate. Then, by matrigel invasion assay, the effect of alendronate on A431 cell invasiveness was studied. All three bisphosphonates were found to inhibit cell proliferation dose- and time-dependently. The most potent molecule was alendronate. The invasion test demonstrated that alendronate also inhibited cell invasion in a Boyden chamber. These data suggest that alendronate may have beneficial effects in the treatment of carcinomas exhibiting important angiogenesis.     

Pamidronate prevents the development of skeletal metastasis in nude mice transplanted with human breast cancer cells by reducing tumor burden within bone

Pamidronate is used routinely in the treatment of established bone metastasis. However, pamidronate has not yet been assessed in the prevention of osteolytic bone metastasis and its precise mechanism of action in this disorder remains to be established. In the present study, pamidronate or vehicle alone was administered subcutaneously to nude mice either simultaneously or as post intracardiac injection of the human breast cancer MDA-MB-231 cells. Radiographs were used first to assess the presence of osteolytic bone metastases. Kaplan-Meier analysis demonstrated that animals treated with pamidronate early, but not late, showed a slower progression of bone metastases and hind limb paralysis than did vehicle-treated animals. Mann-Whitney analysis showed that only 44.4% of mice treated with pamidronate at the time of tumor cell inoculation developed bone metastases as compared to over 80% (p<0.05) of mice receiving vehicle alone. We then analyzed the number of bone lesions and their volume at time of sacrifice by bone histomorphometry. In contrast to X-ray analysis, morphometric analysis indicates that the number of lesions within bone was similar in pamidronate and vehicle-treated mice but that the lesions were significantly smaller and therefore, often not visible on radiographs. These results demonstrate that pamidronate is effective in reducing tumor burden in breast cancer metastatic to bone and is most effective as a preventative agent when administered closest in time to implantation of tumor cells. Our data also suggest that pamidronate acts mainly by inhibiting the growth of established bone metastatic lesions but has no effect on the metastatic spread itself.     

H1 histamine receptor antagonists induce genotoxic and caspase-2-dependent apoptosis in human melanoma cells

Previously, we found that the H1 histamine receptor antagonist diphenhydramine induces apoptosis in human acute T-lymphocytic leukemia cells. Since histamine has been shown to act as a growth factor in malignant melanoma cells, we decided to evaluate the in vitro effect of diphenhydramine and other H1 histamine receptor antagonists, such as terfenadine, astemizol and triprolidine on four malignant human melanoma cell lines. These antagonists were found to induce apoptotic cell death in all four melanoma cell lines. Apoptosis was determined by assessment of phosphatidylserine exposure on the surface of the cells and nuclear fragmentation. Importantly, H1 antagonist treatments did not adversely affect the viability of human melanocytes and murine fibroblasts at the same doses and duration of exposure. Treatment of melanoma cells with terfenadine induced DNA damage and caspases 2, 3, 6, 8 and 9 activation. Furthermore, the general caspase inhibitor (z-VAD-FMK) and a selective inhibitor of caspase-2 (z-VDVAD-FMK) protected melanoma cells from terfenadine-induced apoptosis. In contrast, the caspase-8 inhibitor (z-IETD-FMK) was ineffective. In addition, we found that mitochondria are involved in TEF-induced apoptosis, characterized by the dissipation of the mitochondrial transmembrane potential, the release of cytochrome c into the cytosolic compartment and caspase-9 activation. On the basis of these results we conclude that H1 histamine receptor antagonists induce apoptosis in human melanoma cells but not in normal melanocytes and embryonic murine fibroblasts; this apoptosis appears to be caspase-2-dependent and involves the mitochondrial pathway. The present results may contribute to the elaboration of novel therapeutic strategies for the treatment of malignant human melanoma.     

The anti-tumour activity of bisphosphonates

Bisphosphonates are stable analogues of pyrophosphate (PPi), an endogenous regulator of bone mineralisation. A number of placebo-controlled trials have demonstrated their positive impact on skeletal-related events (SRE) that occur as a consequence of metastatic or myelomatous bone disease. Based upon their chemical structure bisphosphonates can be classified into nitrogen-containing bisphosphonates, (N-bisphosphonates) (for example zoledronate and pamidronate) and non-nitrogen containing (for example, clodronate and etidronate), which more closely resemble PPi. Clinical trials investigating bisphosphonates in the preventative setting have shown bisphosphonates to not only delay occurrence of bone metastases in certain cancers, but in one trial, occurrence of non-osseous lesions was delayed, and survival was prolonged. Other trials however have shown the opposite. Likewise, in animal models of cancer and metastases, conflicting results have been obtained. In vitro work has concentrated on bisphosphonates direct action upon tumour cells and has found a variety of anti-tumour effects such as apoptosis induction, inhibition of cell growth, inhibition of invasive behaviour and inhibition of angiogenic factors. Furthermore it would appear that bisphosphonates have the potential to enhance anti-tumour activity of known cytotoxic drugs. Ongoing research aims to assess this further, in addition to determining more precisely the role of adjuvant bisphosphonates in cancers such as breast and prostate cancer.     

Management of bone metastases in breast cancer

Opinion statement Patients with advanced breast cancer who develop bone metastases suffer an ongoing risk of skeletal complications that can have a significant impact on their quality of life (QoL). These complications include bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM), a potentially life-threatening condition. Treatment options include radiotherapy to palliate bone pain and/ or prevent impending fracture, orthopedic surgery to prevent or repair fractures, analgesics, and bisphosphonates, which can significantly reduce the risk of skeletal complications and delay their onset. Of the known bisphosphonates, zoledronic acid is the most potent. Since its regulatory approval in the United States and Europe in 2001, zoledronic acid (4 mg by 15-minute infusion) has become widely used and has replaced pamidronate (90 mg by 2-hour infusion) as the standard of care for treating bone metastases from breast cancer and bone lesions from multiple myeloma. Zoledronic acid has also demonstrated significant long-term benefits in randomized trials in prostate cancer and other solid tumors, whereas other bisphosphonates have failed. In long-term, phase III clinical testing, zoledronic acid provided significant treatment benefits beyond those of pamidronate in patients with breast cancer and demonstrated a safety profile comparable with pamidronate. Therefore, zoledronic acid is now recommended from the first diagnosis of bone metastasis. Other intravenous bisphosphonates include clodronate and ibandronate. Both are approved in Europe, but their efficacy relative to pamidronate and zoledronic acid is not known.     

Evolving role of bisphosphonates in women undergoing treatment for localized and advanced breast cancer

Breast cancer commonly metastasizes to bone, producing hypercalcemia, pathologic fractures, spinal compression, and pain that increase morbidity and affect the patient's mobility and quality of life. The use of bisphosphonates like pamidronate and zoledronic acid inhibits osteolytic activity caused by bone metastases. The use of bisphosphonates to prevent bone loss and preserve bone health in the adjuvant setting in women with breast cancer undergoing hormonal therapy with aromatase inhibitors or ovarian suppression is being actively investigated. Interestingly, clodronate, an oral bisphosphonate, has been shown in 2 trials to decrease the risk of recurrence in women with early-stage breast cancer, suggesting a direct or indirect antitumor effect of bisphosphonates. Trials to confirm the antitumor effects of bisphosphonates are currently ongoing. Prolonged intravenous bisphosphonate use has been associated with a rare risk of osteonecrosis of the jaw. Recommendations for management of this condition are discussed.     

Bisphosphonates regulate cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line

Local growth of osteosarcoma involves destruction of host bone by proteolytic mechanisms and/or host osteoclast activation. Osteoclast formation and activity are regulated by osteoblast-derived factors such as the osteoclast differentiating factor, receptor activator of NF-kappaB ligand (RANKL) and the inhibitor osteoprotegerin (OPG). We have investigated the in vitro effects of bisphosphonates on a clonal rat osteosarcoma cell line. The aminobisphosphonate pamidronate was added to UMR 106-01 cell cultures (10(-8)M to 10(-4)M up to 5 days). The non-aminobisphosphonate clodronate was administered for the same time periods (10(-6)M to 10(-2)M). Cell proliferation, apoptosis and mRNA expression was assessed. Both agents inhibited cell proliferation in a time- and dose-dependent manner. ELISA analysis demonstrated an increase in DNA fragmentation although there was no significant dose-related difference between the doses studied. Bisphosphonate-treated cultures had a greater subpopulation of cells exhibiting morphological changes of apoptosis. Expression of mRNA for osteopontin and RANKL was down-regulated by both agents, while the expression of mRNA for alkaline phosphatase, pro-alpha1(I) collagen and OPG was not altered. Out in vitro work suggests the bisphosphonates not only have direct effects on osteosarcoma cell growth and apoptosis, but also, by altering the relative expression of osteoclast-regulating factors, they may inhibit the activity of osteoclasts and their recruitment.     

Additive antitumor activities of taxoids in combination with the bisphosphonate ibandronate against invasion and adhesion of human breast carcinoma cells to bone.

A very common metastatic site for breast carcinoma is bone. Metastatic breast carcinoma cells stimulate osteoclast-mediated bone resorption leading to osteolysis. Bisphosphonates are powerful inhibitors of osteoclast activity, and are therefore used in combination with standard chemotherapy or hormonal therapy for the treatment of cancer-associated osteolytic metastases. However, there may be an added beneficial effect of the bisphosphonates, that is, additive or synergistic activities with cytotoxic agents. Here, we investigated the effects of the bisphosphonate ibandronate in combination with taxoids (taxol and taxotere) on induction of apoptosis, invasion and adhesion of breast carcinoma cells to bone. Ibandronate did not induce apoptosis of human MDA-MB-231 breast carcinoma cells, nor did it enhance the effectiveness of taxoid-induced apoptosis in MDA-MB-231 cells. In contrast, ibandronate enhanced the antitumor activity of taxoids against invasion and cell adhesion to bone. Our findings raise the interesting possibility that the combination of bisphosphonates and taxoids may be useful for the treatment of patients with cancer types that are known to metastasize preferentially to bone.     

双膦酸盐抗血管形成机制研究进展

双膦酸盐具有直接抗肿瘤和抗血管形成作用,具体机制仍未肯定.现有研究认为双膦酸盐通过干扰甲羟戊酸信号通路的关键激酶,使小G蛋白异戊酸化受阻等机制抑制内皮祖细胞分化和小管样形成,阻止血管发生;抑制血管内皮细胞的增殖、黏附和迁移能力,干扰血管形成;调节肿瘤血管形成细胞因子分泌,抑制血管形成相关基因等功能发挥其抗血管形成作用.     

Propriétés antitumorales du bisphosphonate zolédronate et implications thérapeutiques potentielles en clinique

Zoledronate, just as other bisphosphonates, inhibit osteoclast mediated bone resorption. This is the reason why they are used in the treatment of bone metastasis, in order to block osteolysis. Zoledronate and some other bisphosphonates (clodronate, pamidronate, ibandronate, alendronate, risédronate, minodronate) also exhibit antitumor properties in vitro. They act directly on tumor cells by blocking tumor cell adhesion, invasion and proliferation, and by inducing tumor cell apoptosis. However, their high bone mineral affinity decreases their bioavailability to a significant extent and, thus, should weaken their in vivo antitumor potential. Despite of this, several studies (most of them being performed with zoledronate) show that bisphosphonates have an in vivo antitumor activity. This review focuses on zoledronate and on results obtained in several experimental models showing that this bisphosphonate interferes with the growth of tumors and metastases which are thriving in tissues others than the skeletal tissue. The significance of these findings is discussed in the light of several ongoing clinical trials which examine the benefits of using zoledronate and other bisphosphonates in the adjuvant treatment of cancers at an early stage of the disease.