Bisphosphonates in cancer therapy

Cancer Letters 257 (2007) 16–35 www.elsevier.com/locate/canlet

Mini-review

Bisphosphonates in cancer therapy Verena Stresing *, Florence Daubine´, Ismahe`ne Benzaid, Hannu Mo¨nkko¨nen, Philippe Cle´zardin INSERM, Research Unit U.664, Faculte´ de Me´decine Laennec, Rue Guillaume Paradin, F-69372 Lyon cedex 08, France Universite´ Claude Bernard Lyon 1, F-69622 Villeurbanne, France Received 24 April 2007; received in revised form 29 June 2007; accepted 2 July 2007

Abstract Bisphosphonates are the standard of care in the treatment of malignant bone diseases, because of their ability to inhibit osteoclast-mediated bone destruction. We review here preclinical evidence that bisphosphonates also exert direct antitumour effects and antiangiogenic properties. Furthermore, we describe new insights on how bisphosphonates may act synergistically in combination with antineoplastic drugs or cd T cells to exhibit antitumour activity. These findings reveal new exciting possibilities to fully exploit the antitumour potential of bisphosphonates in the clinical practice.  2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Bisphosphonate; Bone; Metastasis; Cancer

1. Introduction Bisphosphonates have long become an integral part of therapy in benign and malignant metabolic bone diseases, such as Paget’s disease, osteoporosis and tumour-associated hypercalcaemia and osteolysis, because of their ability to inhibit bone loss. Bisphosphonates are analogues of the naturally occurring inorganic pyrophosphate (PPi) in which the phosphoanhydride linkage (P–O–P) has been replaced by a non-hydrolysable P–C–P bond. Two covalently bound side chains (referred to as R1 * Corresponding author. Address: INSERM, Research Unit U.664, Faculte´ de Me´decine Laennec, Rue Guillaume Paradin, F-69372 Lyon cedex 08, France. Tel.: +33 4 78 77 87 73; fax: +33 4 78 77 87 72. E-mail address: [email protected] (V. Stresing).

and R2) at the central carbon atom give rise to a great variety of possible structures and contribute to their different relative potencies (Fig. 1). Like their natural analogue, bisphosphonates are capable of binding divalent cations like Ca2+ in a tridentate manner, by coordination of the two phosphonate groups and the R1 substituent (preferably a hydroxyl group) [1]. The ability to chelate Ca2+ ions is the basis for the bone-targeting property of bisphosphonates, whereas the structure and stereochemistry of the R2 chain determines their efficacy to inhibit the activity of bone-resorbing cells (osteoclasts), leading to inhibition of bone resorption. Bisphosphonates can be grouped into two classes according to their mechanisms of action. Those with a simple R2 side chain lacking a nitrogen-containing functional group (such as clodronate) are metabolized intracellularly into non-hydrolysable ATP

0304-3835/$ - see front matter  2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2007.07.007

V. Stresing et al. / Cancer Letters 257 (2007) 16–35

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Fig. 1. Structures of the bisphosphonates and apomine described in this review.

analogues that accumulate in the cytosol and subsequently induce apoptosis [1]. Nitrogen-containing bisphosphonates (N-BPs; such as pamidronate, risedronate or zoledronate), which are several orders of magnitude more potent in inhibiting bone resorption than their non-nitrogen counterparts, act on the mevalonate pathway by inhibiting the key enzyme farnesyl diphosphate synthase (FPP synthase), thereby depleting the cell of the isoprenoid lipids FPP and geranylgeranyl diphosphate (GGPP) (Fig. 2) [2]. FPP and GGPP are required for the post-translational prenylation of members of the small G-protein superfamily, including small GTPases such as Ras, Rac and Rho [3]. Isoprenylated proteins are important signalling proteins that regulate a variety of cellular processes essential for normal cell activity and survival, and have also been shown to have a central role in some cancers [3]. As inhibitors of bone resorption, bisphosphonates have become the standard of care in the treatment of patients with cancer-induced bone diseases.

However, it is now becoming clear that bisphosphonates also exhibit direct and indirect antitumour effects in preclinical models [4,5]. In this review, we focus on current preclinical evidence for the antitumour activity of N-BPs and discuss the possible mechanisms of action of bisphosphonates (and bisphosphonate analogues) and their application in cancer treatment. 2. Direct antitumour effects of N-BPs 2.1. Tumour cell proliferation and induction of apoptosis Bisphosphonates have shown anticancer activity against a broad variety of tumour cell lines in vitro. The potency of several N-BPs to inhibit cancer cell proliferation and increase apoptosis has been demonstrated in breast, prostate, ovarian, bladder, hepatoma, osteosarcoma, leukemia, melanoma as well as myeloma cells [6–14]. The main

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Fig. 2. Inhibition of the mevalonate pathway. N-BPs inhibit the key enzyme FPP synthase, responsible for the farnesylation as well as geranylation of small G-proteins. Statins block the conversion of HMG-CoA to mevalonate by inhibition of HMG-CoA reductase, thereby preventing protein prenylation. Apomine, a 1,1-bisphosphonate ester, also acts as an inhibitor of HMG-CoA. Farnesyl transferase inhibitors (FTI) inhibit FTase, thereby preventing farnesylation of small G-proteins.

mechanism through which N-BPs induce apoptosis seems to be via the mevalonate pathway by blocking the prenylation of small GTPases of the Ras and Rho family [7,11,12] (Fig. 2). Much attention has been paid to Ras-mediated apoptosis induction, because of the importance of the oncogene Ras in the regulation of cancer cell proliferation. N-BPs such as zoledronate and pamidronate inhibit the farnesylation of Ras, thereby disrupting its interaction with the cell membrane, which consequently leads to the downregulation of Ras signalling and of Akt and ERK1/2-dependent survival pathways. These changes ultimately cause the release of cytochrome c, the degradation of poly (ADP ribose) polymerase (PARP) and the activation of caspases [15,16]. Furthermore, zoledronate seems to induce apoptosis and growth arrest in tumour cells inde-

pendently of their p53 status [17]. Minodronate (YM529), a novel bisphosphonate, also acts on the mevalonate pathway via inhibition of Ras-prenylation (activated primarily after farnesylation) and was also shown to inhibit geranylgeranylation of Rap1A, thereby reducing the growth of several bladder cancer cell lines in vitro [9]. The mechanism through which N-BPs induce apoptosis can vary according to cell type and/or bisphosphonate used. Recently, Ory et al. [18] described a novel atypical apoptosis mechanism independent of caspase activation in osteosarcoma cells treated with zoledronate. Cell death was characterized by an increase in Bax and a decrease in Bcl-2 expression, nuclear alterations as well as the activation of a mitochondrial pathway via translocation of apoptosis-inducing factor (AIF) and endonuclease-G. Mo¨nkko¨nen

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and colleagues [19] proposed a novel direct mechanism of apoptosis induction by N-BPs, based on the inhibition of the mitochondrial adenine nucleotide translocase (ANT), which is known to be involved in the induction of apoptosis [20]. Although N-BPs, unlike non-N-BPs such as clodronate, are not metabolized to AppCp-type metabolites, Mo¨nkko¨nen et al. showed that N-BPs induce the formation of ApppI – a novel ATP analogue – as a consequence of the inhibition of the mevalonate pathway in cells. Similarly to the ATP analogues of non-N-BPs [20], ApppI is able to induce direct apoptosis through blockade of the mitochondrial ANT [19]. The authors therefore suggest that some very potent N-BPs (e.g. zoledronate, risedronate) are able to induce apoptosis both indirectly via the inhibition of protein isoprenylation, and directly via inhibition of ANT by ApppI. Furthermore, Mo¨nkko¨nen et al. have shown the considerable variation of ApppI formation by zoledronate between different cancer cell lines, and thus, suggested that the efficiency of N-BPs against tumour cells may vary according to the extent of accumulation of the pro-apoptotic ApppI molecule within the cells [21]. The novel bisphosphonate analogue apomine, a 1,1-bisphosphonate ester, has been shown to induce apoptosis in several cancer cell lines via inhibition of the Ras/MAPK pathway and activation of caspase-3 [22]. However, recent studies demonstrate that apomine is also able to exhibit its pro-apoptotic effect independently of the mevalonate pathway. In breast cancer cells, treatment with apomine causes growth inhibition associated with caspase and p38 MAPK activation without affecting Ras membrane localization [23]. In agreement with these data, Pourpak et al. [24] demonstrated that apomine does not alter N-Ras farnesylation in human melanoma cells. The authors propose a novel mechanism independent of apoptosis, in which cell death is induced through a plasma membrane-mediated cytolytic pathway. Another potent mechanism through which bisphosphonates can exert their antiproliferative effect in cancer cells is cell cycle perturbation. In this regard, zoledronate seems to be particularly effective at inhibiting cell growth by inducing cell cycle arrest in the S-phase, often but not always accompanied by apoptosis induction via activation of caspases [12,25]. Other bisphosphonates such as incadronate, minodronate (YM529), alendronate and risedronate have also been reported to induce S-phase cell cycle arrest followed by apoptosis via

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inhibition of the mevalonate pathway, albeit less frequently [26,27]. More research will be necessary to elucidate the different pathways by which N-BPs inhibit cell growth and induce apoptosis and to uncover the molecular targets of N-BPs underlying these mechanisms. 2.2. Tumour cell adhesion and invasion Metastasis formation, the spread of cancer from a primary tumour to distant organs, involves multiple steps including extravasation of malignant cells from the blood stream and invasion of tumour cells in the host tissue [28,29]. Tumour invasion requires adhesion of cancer cells to the extracellular matrix (ECM), pericellular proteolysis of the ECM and subsequent migration of cancer cells [30,31]. Bisphosphonates have been shown to inhibit adhesion of breast and prostate cancer cells to the ECM in vitro, thereby preventing the spreading of cancer cells to bone [32,33]. The relative potencies of NBPs at inhibiting the adhesion of cancer cells to bone correspond hereby to their relative ability to inhibit osteoclastic resorption in vivo. In vitro, the concentrations needed to achieve this effect are much lower than those required to induce apoptosis in cancer cells. The mechanisms behind the antiadhesive properties of N-BPs remain unknown. It has been suggested that bisphosphonates could modulate the expression of cell adhesion molecules (such as laminins) and cell surface receptors (such as integrins or cadherins). Zoledronate has been shown to reduce the adhesion of prostate cancer cells to the mineralized bone matrix via inhibition of G-protein prenylation, in particular geranylgeranylation [34]. Small G-proteins such as Ras and Rap are important signalling molecules with multiple cellular roles, often related to integrin function [35]. Thus, by inhibiting protein prenylation, NBPs may ultimately affect the expression of key cell surface receptors, thereby preventing cell adhesion to bone. A direct effect of zoledronate on the expression of cell surface receptors has recently been demonstrated in bone marrow stromal cells [36]. Treatment of bone marrow stromal cells with zoledronate resulted in a significant reduction of VCAM-1 (CD106), ICAM-1 (CD54), CD49d and CD40 integrin-expression. Downregulation of ICAM-1 and VCAM-1, which mediate cell–cell interactions, is of particular interest, since it can affect tumour proliferation, survival, and local

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secretion of IL-6. Moreover, these molecules also serve as transmembrane links to the cytoskeleton and are able to trigger a variety of signal transduction events often acting in concert with G-proteins such as Rac and Ras (for a review on integrins, see ref. [37]). Numerous studies have also described the ability of bisphosphonates to inhibit cancer cell invasion in vitro at micromolar concentrations [4,38,39]. It has been suggested that this mechanism is linked to RhoA-inhibition (via specific inhibition of geranylgeranylation) and also involves the downregulation of specific chemokine receptors associated with the development of bone metastases [40]. In addition, bisphosphonates may inhibit the activity of metalloproteinases (MMPs) which are required for the proteolytic degradation of the ECM by cancer cells [6,41]. For instance, Hashimoto et al. [42] demonstrated that alendronate inhibits ovarian cancer cell invasion in visceral organs via inhibition of MMP-2 activity. Similarly, Montague et al. [43] have shown that zoledronate causes a significant decrease of MMP-7 expression levels in prostate cancer cells, whereas TIMP-2 (Tissue Inhibitor of Matrix Metalloproteinase 2) expression is substantially increased. Although the mechanisms of MMP inhibition by bisphosphonates remain unclear, the authors propose that it may be through the mevalonate pathway by inhibiting Ras/Rho/ MAPKK signalling. Additionally, bisphosphonates may inhibit the proteolytic activity of MMPs by chelating zinc from the active site of the enzyme [6]. However, this effect only occurs when high concentrations (10 4 mol/L) of bisphosphonates are used. Even though changes in MMP levels have only been observed in vitro at high N-BP-concentrations, inhibition of MMP secretion may be an alternative mechanism through which bisphosphonates inhibit cancer cell invasion. 3. In vivo antitumour effects of bisphosphonates 3.1. Effects of N-BPs on skeletal lesions There is now ample evidence that N-BPs also exert antitumour effects in vivo, reducing skeletal tumour burden and metastatic incidence in bone [4]. In animal models of bone metastasis, the anticancer activity of N-BPs has been attributed to their ability to inhibit osteoclasts, thereby reducing the release of bone-derived growth factors from resorbed bone, which are required for skeletal

metastasis [44,45]. In addition to being effective against osteolytic changes, third-generation N-BPs have also been shown to impair prostate cancerinduced osteoblastic changes in vivo [38,46]. In models of multiple myeloma (MM), treatment with N-BPs such as pamidronate or zoledronate has been shown to decrease bone resorption and inhibit myeloma cell growth [6,47], which consequently may lead to a reduced tumour burden and an increased overall survival of mice [48]. Because of their high affinity to mineralized bone, bisphosphonates may also target bone tumours – such as osteosarcoma, chondrosarcoma or Ewing sarcoma – inhibiting tumour growth and progression [49–51]. However, the high bisphosphonate doses mostly used in animal studies are often incompatible with the current clinical regimens that have been approved for the treatment of patients suffering from bone disease. We recently demonstrated that low dosage of zoledronate, administered to animals on a daily or weekly intermittent schedule, not only inhibits bone destruction, but also exhibits antitumour effects, whereas treatment of animals with a single clinical dose inhibits bone destruction, but not tumour burden [52]. Our study indicates that a continuous or frequent low-dose therapy with bisphosphonates might affect tumour cells directly, and therefore represents the rationale of a low intermittent regime of bisphosphonates. It remains to be seen whether the results achieved in these experimental studies can be extrapolated to the clinical practice. 3.2. Effects of N-BPs on soft tissue tumours The efficacy of bisphosphonates on tumour cells residing in extra-osseous sites is still being debated. Only a small number of studies have demonstrated that N-BPs exhibit antitumour activity on soft tissue tumours in vivo (Table 1). Using a transgenic mouse model of cervical cancer, Giraudo et al. [53] demonstrated that zoledronate is able to exert a beneficial antitumour effect, reducing the growth of cervical tumours and inhibiting the progression of premalignant lesions to invasive carcinoma. However, the authors chose a daily regimen (calculated to be equivalent to 6 mg in humans) rather than monthly administrations of zoledronate as approved for the treatment of bone metastases in humans (usually 4 mg), thereby far exceeding the total cumulative dose recommended in the clinical practice. The first report for the in vivo efficacy of N-BPs against primary

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Table 1 Effects of bisphosphonate treatment in animal models A. N-BPs and soft tissue tumours Tumour

N-BP (dosisa)

Type of effect

Ref.

Breast cancer (MDA-231 cells)

Ris (0.4, 4, +40 lg/d s.c.) (therapeutic or preventive) Iba (4 lg/d s.c.)

[58] [59]

Zol (2 lg/d s.c.)

Inhibition of bone metastasis and tumour burden in bone, no effect on breast tumour Inhibition of bone metastasis and tumour burden in bone, no effect on breast tumour Inhibition of tumour growth and tumour progression

Zol (1.6 lg i.v., 3·/wk) Min (5 lg/d i.p.) Min (ca. 1 or 3.4 lg, transurethally)

Inhibition of tumour growth Inhibition of tumour growth Inhibition of tumour growth

[54] [14] [9]

Pam (20 lg/d i.p.)

Inhibition of tumour growth

[11]

Zol (10 lg i.p., 3·/wk) or Ris (300 lg i.p. every 6 days)

Inhibition of tumour growth; increase in overall survival

[55]

Breast cancer (MDA-231 cells) Cervical carcinoma (K14HPV16 transgenic mice) SCLC (SBC-3 cells) Melanoma (G361 cells) Bladder cancer (UM-UC-3 cells) Hepatocellular carcinoma (PLC/PRF/5 cells) Mesothelioma (AB12 and AC29 cells) B. N-BPs and visceral metastasis Primary tumour SCLC, systemic model (SBC-5 cells, i.v.) Bladder cancer, systemic or orthotopic (UM-UC-3 cells, i.c./injection in bladder) Breast cancer (4T1 cells) orthotopic inoculation Breast cancer, systemic model (MDA-231AD cells, i.c.) Osteosarcoma, systemic model (POS1 cells, i.v.) Breast cancer, orthotopic model (4T1 cells, i.m.f.p.)

[53]

Metastasis

N-BP (dosisa)

Type of effect

Ref.

Lymph node, lung, liver, kidneys, bone Bone, visceral

Min (2 lg once, i.v.)

Reduction of bone metastasis only, no effect on visceral metastasis

[60]

Bone, adrenal

Iba (4 lg/d, s.c.)

Lung

Zol (2 lg 5·/wk, 2 lg or 20 lg 2·/wk) Zol (0.5 or 5 lg, 1 or 5·, i.v.)

Reduction of bladder tumour growth and bone metastasis, reduction of visceral metastasis (not significant) Reduction of bone metastasis, no effect on visceral metastasis Reduction of bone metastasis, Increase of adrenal metastasisb Reduction of lung metastasis, increase in overall survival Reduction of bone metastasis, reduction of lung metastasisc

[9]

Bone, lung

Min (1.6 lg/wk, s.c.) Min (ca. 1 or 3.4 lg, 5· transurethally) Iba (4 lg/d, s.c.)

Bone, lung, liver

[61] [61] [51] [62]

Abbreviations: Iba, ibandronate; MIN, minodronate; Pam, pamidronate; Ris, risedronate; Zol, zoledronate. a All doses are calculated per mouse, estimating an average body weight of 20 g/mouse. b Only in a preventive setting. c Only with frequent dosing schedule.

tumours in small cell lung cancer (SCLC) was given by Matsumoto et al. [54]. Administration of zoledronate alone or in combination with several anticancer agents for SCLC significantly inhibited SCLC tumour growth in nude mice previously inoculated with SBC-3 cells. However, the in vivo experimental zoledronate doses in this study also exceeded the recommended dose for humans. Treatment with high doses of minodronate was shown to suppress melanoma growth and improve survival in G361-xenografted nude mice [14]. The authors suggested that these effects were achieved through two independent mechanisms: (1) by blocking VEGF signalling in endothelial cells and (2) by inducing apoptosis in melanoma cells. Similarly, pamidronate treatment of nude mice previously

inoculated with hepatocellular carcinoma cells was also shown to significantly reduce tumour growth in mice by promoting the apoptosis of human HCC in vivo [11]. Sato et al. [9] investigated the growth-inhibitory effect of minodronate in bladder cancer, using an orthotopic mouse model in which UM-UC-3/luc cells were implanted into the bladder, in order to examine the effect of intravesical administration. High doses of minodronate (ca. 1 or 3 lg/mouse) were shown to exert significant anticancerous effects. When administered on a daily treatment schedule (five injections of minodronate), the lower dose treatment was sufficient to effectively inhibit bladder tumour growth, indicating that local administration of minodronate in the restricted environment of the bladder may provide a high con-

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centration exposure of the agent to the target cells over a limited time. Recently, Wakchoure et al. [55] showed that zoledronate and risedronate inhibit mesothelioma tumour growth in vivo and prolong the survival of mesothelioma-bearing mice, when administered in a treatment setting. The authors suggest that the growth-inhibitory effects of N-BPs are regulated by excess Ca2+ in a cell and bisphosphonate-specific fashion. Since many tumour types are calcified, this may be of physiological relevance. Bisphosphonates might be able to accumulate in calcified tumours that are growing at visceral sites [56]. Supporting this hypothesis, bisphosphonates have been shown to accumulate in the arterial walls of atherosclerotic animals, where they inhibit atherogenesis because of their ability to reduce arterial calcification [57]. However, other experimental studies using high doses of bisphosphonates (i.e. risedronate and ibandronate) did not show any convincing inhibitory effects on growth of subcutaneous breast tumour xenografts [58,59] (Table 1, part A). Similarly, the effects of N-BPs on visceral metastases are still unclear (Table 1, part B). While minodronate has an obvious antitumour effect in several experimental models of bone metastasis, no effect on the development of visceral metastases (lymph node, lung, liver) has been reported in animals bearing small cell lung [60] or bladder tumours [9]. In the same vein, a preventive or curative treatment of mice bearing 4T1 mammary tumours with ibandronate inhibits the onset of bone metastasis, whereas it does not affect lung metastases formation [61]. In mice bearing MDA-231 tumours, a preventive administration of ibandronate was shown to even further increase adrenal metastases. However, this effect was not observed in treatment settings that more closely reflect the clinical situation (therapeutic treatment, as well as co-administration of doxorubicin) [61], suggesting that N-BPs are at least unlikely to have adverse effects on visceral metastases. There are some in vivo studies with zoledronate, however, in which a beneficial inhibitory effect on the formation of visceral metastases has been observed [50,62]. For instance, in a murine model of lung metastases induced by i.v. injection of osteosarcoma POS-1 cells, the administration of zoledronate was demonstrated to significantly decrease osteosarcoma-induced lung metastasis in vivo, thereby prolonging overall survival of the animals [50]. In a model of syngeneic immunocompetent mice bearing 4T1 mammary tumours, repeated

injections of high doses of zoledronate were found to reduce the formation of spontaneous metastases in visceral organs (lungs and liver) as well as in bone and prolong survival of the animals [62]. In contrast, lung and liver metastases were not affected when a single injection of zoledronate was used, suggesting that a more frequent dosing schedule is probably required to achieve antitumour activity with bisphosphonates. Overall, the in vivo antitumour activity of bisphosphonates varies a lot according to the type of tumour, the sort of bisphosphonate used, and the different bisphosphonate-dosing regimens administered to animals. Because of the rapid uptake of bisphosphonates in bone, we surmise that circulating concentrations of this drug may be too low to be effective on the growth of soft tissue malignancies. Conversely, bisphosphonate therapy with frequent dosing intervals may allow a more prolonged exposure of soft tissues to these drugs, thus enabling a direct effect on tumour cells. 4. Indirect antitumour effects of bisphosphonates 4.1. Antiangiogenic effects of N-BPs Angiogenesis, the formation of new blood vessels from existing ones, is a fundamental step in tumour development that involves a series of events, including endothelial cell proliferation, migration and their realignment to form new capillaries [63]. In addition, bone marrow-derived endothelial progenitor cells mobilize to the bloodstream and contribute to the vascularization of primary tumours [64]. Several N-BPs have been reported to inhibit vascular endothelial cell functions in vitro and in vivo. For instance, zoledronate, risedronate, alendronate, ibandronate and clodronate have been shown to reduce endothelial cell proliferation and migration, and to decrease capillary-like tube formation by human umbilical vein endothelial cells (HUVECs) in vitro [65–68]. Molecular mechanisms through which bisphosphonates inhibit endothelial cell functions are likely to include suppression of focal adhesion assembly [67,68], inhibition of Rho geranylgeranylation [67] and suppression of sustained activation of protein kinaseB/Akt [66]. Bisphosphonates do not however modulate the cell surface expression of integrins that are associated with signalling through focal adhesion kinase and Rho [67]. In vivo, zoledronate and ibandronate, but not clodronate (a non-N-BP) inhibit the

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revascularization of the prostate gland under testosterone stimulation in castrated rats [64]. In addition, the treatment of mice with zoledronate inhibits the vascularization of subcutaneous tissue chambers impregnated with basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) [66]. The mechanisms by which N-BPs exert their antiangiogenic effects and particularly their role in VEGF signalling have not yet been clearly understood. Yamagishi et al. [14] demonstrated in a murine melanoma model that minodronate inhibits melanoma growth by suppressing VEGF signalling through blockade of Ras activation and NADPH oxidase-mediated reactive oxygen species (ROS) generation. Zoledronate may also suppress tumour-associated angiogenesis in a transgenic HPV/E2 mouse model of cervical cancer by inhibiting MMP-9-mediated mobilization of stromal VEGF [53]. In accordance with these findings, N-BPs were reported to reduce circulating VEGF in cancer patients [69,70]. By contrast, although alendronate inhibits tumour angiogenesis in animals bearing ovarian tumour xenografts, this reduction of the vascularization upon bisphosphonate treatment was not associated with an inhibition of tumour-derived VEGF expression [67]. Additional inhibitory mechanisms of bisphosphonates, such as interference with the proliferation and/or mobilization of bone marrow-derived endothelial progenitor cells, might account for their observed antiangiogenic properties. 4.2. Immunomodulatory effects of N-BPs Bisphosphonates also have the ability to target cancer cells by modulating the immune system. Several N-BPs, such as pamidronate, ibandronate, alendronate, risedronate as well as zoledronate, have been shown to induce a significant expansion of cd T cells, both in vitro and in vivo, mainly affecting the most abundant subset of Vc9Vd2 cells [71– 74]. In contrast, non-N-BPs, like etidronate and clodronate, have failed to show this stimulatory effect on cd T cells. Similarly, bisphosphonate analogues lacking one of the two phosphate groups lose their stimulatory activity, suggesting that both, the nitrogen atom and the P–C–P moieties are essential for the activation of cd T cells by N-BPs [75,76]. T lymphocytes bearing a cd T cell-receptor (TCR) represent a minor subset of human peripheral blood T cells (1–5%). As opposed to antigen-recognition by ab T cells, cd T cell-specific antigens do

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not need to be processed by professional antigenpresenting cells (APC), and do not require binding presentation by classical major histocompatibility complex (MHC) molecules. Instead, cd T cells recognize tumour cell-expressed ligands that are not detected by conventional ab T cells, and are therefore able to exert potent MHC-unrestricted cytotoxic effector activity toward various tumour cells, especially of hematological origin such as lymphoma or myeloma cells [71,77,78]. In addition, the Vc9Vd2 TCR is directly involved in the recognition of lymphoma and myeloma target cells [79,80]. Since loss of MHC molecules in cancer cells is frequent and often renders the cells resistant to ab T cell-mediated cytotoxicity, stimulation of cd T cells might be a potent approach in anticancer therapy [81]. Preclinical studies have demonstrated that Vc9Vd2 cells expanded in vitro maintain their antitumour activity in vivo upon adoptive transfer into immunodeficient mice transplanted with human tumour cells (e.g. nasopharyngeal carcinoma, melanoma, Daudi lymphoma, pancreatic adenocarcinoma, SCLC and renal cell carcinoma) in combination with N-BP treatment [81–85]. Therefore, an effective T cell-based immunotherapy might involve a double strategy for the potential usage of cd T cells: the in vivo therapeutic application of cd T cell-stimulating N-BPs together with low-dose IL2 against some types of cancers, including lymphoma, myeloma and renal cell carcinoma [86], possibly followed by an adoptive cell transfer of in vitro expanded cd T cells [87]. Indeed, Wilhelm et al. [74] reported a significant proliferation of cd T cells and tumour regression in patients with relapsed/refractory low-grade non-Hodgkin lymphoma or multiple myeloma, when pamidronate was administered together with IL-2. Activation of cd T cells by N-BPs requires cellto-cell contacts with tumour cells and peripheral blood mononuclear cells (PBMC), like monocytes and macrophages [88]. The internalization of NBPs by PBMCs or cancer cells causes the intracellular accumulation of endogenous isoprenoids, such as isopentenyl pyrophosphate (IPP), an upstream substrate of FPP synthase, and ApppI, a novel ATP analogue. (Fig. 3). IPP (or ApppI) is then presented to Vc9Vd2 T cells by an as yet unidentified mechanism, which leads to T cell activation capable of tumour cell killing [74,88,89]. Therefore, N-BPs could be used as an immune therapy, where NBP-induced IPP accumulation in tumour cells might

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Fig. 3. Tumour cell ligands recognized by human cd T cells sensitized with non-peptide agents. The cd T cell-receptor (TCR) recognizes non-peptidic phosphoantigens like IPP or ApppI. IPP/ApppI accumulation is caused by inhibition of FPP synthase with N-BPs. The cd TCR also recognizes ATP synthase (AS) and Apolipoprotein (Apo) A-I. In addition, MICA/MICB, which are frequently expressed on tumour cells, are ligands to the NKG2D receptor in cd T cells. CD6 is a further cd T cell-receptor for the ligand CD166, expressed on some tumour cells. The consequences of activating cd TCRs by ligation include perforin-mediated cytotoxicity as well as the production of cytokines (TNFa, IFN-c), which induces apoptosis in tumour cells and leads to the activation of immune cells (ab T cells, NK T cells).

be a powerful danger signal that activates T cellmediated immune response against tumours [74,90]. Mo¨nkko¨nen and colleagues showed the considerable variation of IPP accumulation between different cancer cells after zoledronate treatment, which may be related to mevalonate pathway activity [21]. As a response to N-BP-mediated T cell activation and proliferation, cd T cells secrete cytokines, such as TNFa and IFN-c (Fig. 3), enhancing antitumour activity by inhibiting tumour cell growth and angiogenesis [71,74]. Vc9Vd2 T cells may also stimulate the activity of NK and NKT cells, macrophages and ab T cells through the secretion of IFN-c [89]. Another mechanism through which cd T cells may mediate cytotoxicity after target cell recognition is the perforin/granzyme pathway [91] (Fig. 3). Vc9Vd2 T lymphocytes also express the activating NK cell receptor NKG2D. This cell surface receptor is important for tumour cell recognition by bisphosphonate-activated cd T cells; it recognizes cancer cells (carcinomas, myelomas, lymphomas) that

express the stress-inducible MHC-I-related MICA/ MICB proteins (Fig. 3) [92–94]. Vc9Vd2 T cells also recognize a complex formed between apolipoprotein (Apo) A–I and ATP synthase (AS), a mitochondrial enzyme which is translocated to the surface of some tumour cell lines, in a TCR-dependent fashion (Fig. 3) [95]. The biological relevance of AS recognition by Vc9Vd2 T cells is still unclear, however, it may involve AS in N-BPs presentation to cd T cells [96]. Another target molecule associated with the activation of cd T cells by N-BP-treated tumour cells may be CD166 (or activated leukocyte-cell adhesion molecule, ALCAM), a cell surface molecule involved in cell–cell interactions through CD166–CD6 binding [97]. Expression of CD166 has been described in malignant melanoma and in various carcinoma cell lines including breast, lung, colon, bladder and prostate [98–102]. Upregulation of CD166 correlates with shortened patient survival suggesting a role for CD166 in tumour progression. Vc9Vd2 T cells constitutively express CD6, a receptor for CD166, and both CD6 and CD166 were

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shown to be involved in the interaction between cd T cells and N-BP-treated tumour cells [103]. Upon treatment of tumour cells with N-BP, cd T cells form synaptic conjugates with tumour cells, in which CD6 and CD166 are recruited together into the center of adhesion site, where they co-localize with cd TCR/CD3. This strongly suggests a direct interaction between CD6 and CD166 in cd TCR/ CD3 mediated cd T cell activation [103]. Recently, Dieli et al. [104] described the in vivo effect of N-BPs on newly identified subsets of Vc9Vd2 cells that display different functional activities: CD45RA+CD27+ naive and CD45RA CD27+ memory Vc9Vd2 cells strongly proliferate but lack immediate effector functions, while CD45RA CD27 Vc9Vd2 cells proliferate poorly but produce IFN-c and exert cytotoxicity [105]. Treatment of patients with bone metastases from breast and prostate cancer with zoledronate expands a subset of effector Vc9Vd2 cells, while dramatically decreasing the naive and memory subsets, whereas the percentage and absolute numbers of Vc9Vd2 cells in PBMCs remain unchanged. This modification of Vc9Vd2 cell subset distribution also leads to functional alterations, such as a decrease in the proliferative activity of Vc9Vd2 cells upon in vitro stimulation with IPP – a property of naive and memory cells – as well as an increase in IFNc-production upon in vivo treatment with zoledronate, mediated by effector cells. The authors therefore conclude that in vivo treatment with zoledronate induces Vc9Vd2 cells to mature toward an IFN-c-producing effector phenotype, which may induce more effective antitumour responses [104]. Patients receiving intravenously administered NBPs often show a ‘‘flu’’-like reaction with low-grade fever and chills after treatment for the first time [106]. The development of this acute-phase response (APR) strengthens the idea that N-BPs indirectly stimulate the activation of Vc9Vd2 T cells. Indeed, the inhibition of FPP synthase in PBMCs leads to the accumulation of IPP, which is then presented to Vc9Vd2 T cells, triggering cd T cell activation and consequently the release of IL-2 or other cytokines such as IFN-c [107]. In contrast, clodronate – a non-N-BP that does not inhibit FPP synthase – is not able to cause IPP accumulation in cells [19]. This might be the main reason why non-NBPs do not evoke APR. In summary, these studies suggest that the anticancer effects of cd T cells may be achieved through three main mechanisms: (1) inhibition of tumour

25

growth by IFN-c secreted from cd T cells, (2) direct killing of cancer cells by perforin (secreted by cytotoxic T lymphocytes) following interaction of cd T cells with cancer cells, and (3) IPP-dependent immunomodulatory mechanism, which has yet to be clarified in vivo. Vc9Vd2 T cells may therefore play a major role in cancer and the stimulation of these cells using N-BPs could be an effective way to combat cancer. 5. Synergistic interactions between N-BPs and cytotoxic agents The use of drug combinations is a well-established principle of cancer therapy because of the perception that these drugs might act synergistically in combination (that is, to provide greater benefit in combination than evidenced by the additive effects of individual drugs). There is some preclinical evidence that the combination of N-BPs with chemotherapeutic or other molecularly targeted anticancer agents may lead to an enhanced antitumour activity (Table 2). 5.1. In vitro models Patients with advanced breast or prostate cancer will often receive chemotherapeutic agents as well as bisphosphonates during the course of their treatment. Many in vitro studies have therefore been completed in breast or prostate cancer models (Table 2). Zoledronate seems to be a promising candidate for a combination treatment with chemotherapeutic drugs commonly used in breast and prostate cancer, such as doxorubicin or taxanes. Co-administration of zoledronate and doxorubicin or taxanes was shown to cause induction of apoptosis in breast and prostate cancer cell lines in a synergistic fashion [108–110]. Furthermore, zoledronate in combination with doxorubicin was shown to drastically reduce cell invasion in breast cancer cells [111]. Importantly, the synergistic actions seem to be sequence- as well as schedule-dependent, whereby the sequence chemotherapeutic drug first, then NBP seems to be the most effective synergistic combination. COX-2 inhibitors used in combination with taxanes effectively inhibit tumour growth [112]. In human breast cancer cells over-expressing the Her2/neu gene, the triple combination docetaxel/ COX-2 inhibitor/zoledronate was shown to even further increase this growth-inhibitory effect com-

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Table 2 Combined effects of bisphosphonates and cytotoxic agents in vitro Cell lines

Agent

N-BP

Type of effect

Synergistic/additive

Ref.

Breast and prostate cancer Breast cancer

Dox

Induction of apoptosis, (Zol > Ale) Inhibition of invasion

Breast cancer Breast cancer

Pac Pac

Zol Zol

Induction of apoptosis Induction of apoptosis

Breast cancer

CMF, EC, ET, EDoc

Growth inhibition

Breast cancer (Her2+) Prostate cancer Breast, prostate and lung cancer Osteosarcoma

Doc + SC-263 Doc Gem, Flu

Zol, Iba Zol Zol Zol

Synergistic, sequence and timing dependent Synergistic, sequence and timing dependent Synergistic Synergistic, sequence and timing dependent Synergistic

[109]

Dox

Zol, Ale Zol

Growth inhibition Induction of cytotoxicity Induction of apoptosis

Additive Additive/synergistic Synergistic

[113] [141] [142]

Pac, Gem, Dox

Zol

Growth inhibition

[114]

Osteosarcoma Myeloma Myeloma

Cisplatin Dexa Sim

Zol Zol Zol

Myeloma Leukemia Leukemia (Ph+) Bladder cancer SCLC

ATRA, INFa IM, HU, AraC, DNR IM Pac, Cisplatin Pac, etop, cisplatin, irinotecan, IM FTI (R115777)

Min Zol Zol Min Zol

Growth inhibition Induction of apoptosis Induction of apotosis, reversion of bortezomid resistance Growth inhibition Growth inhibition Growth inhibition Growth inhibition Induction of apoptosis

Synergistic, sequencedependent Synergistic, p53-dependent Synergistic Synergistic

[116] [121] [120] [9] [54]

Zol, Pam

Growth inhibition, induction of apoptosis

Synergistic Additive Synergistic Synergistic/additive Synergistic Additive (IM) Synergistic

Epidermoid cancer (head/neck, lung)

[111] [108] [110] [140]

[115] [143] [119]

[122]

Abbreviations: Ale, alendronate; AraC, cytarabine; ATRA, all-trans retinoic acid ; CMF, cyclophosphamide/metotrexate/5-fluorouracil; Dexa, dexamethasone; Doc, docetaxel; Dox, doxorubicin; EC, epirubicin/cyclophosphamide; EDoc, epirubicin/doc; ET, epirubicin/ paclitaxel; Etop, etoposide; Flu, fluvastatin; FTI, farnesyl transferase inhibitor; Gem, gemcitabine; HU, hydroxyurea; IM, imatinib mesylate; Pac, paclitaxel; Sim, simvastatin.

pared to docetaxel/COX-2 inhibitor or docetaxel/ zoledronate combinations [113]. In osteosarcoma or multiple myeloma, several studies have reported synergistic interactions between zoledronate and some commonly used chemotherapeutic drugs (Table 2). Zoledronate combined with doxorubicin, paclitaxel or gemcitabine was shown to inhibit osteosarcoma cell growth synergistically and in a sequence-dependent fashion; pretreatment of the cells with zoledronate further increases the sensitivity of the cells to the chemotherapeutic drug [114]. In combination with cisplatin, the presence of p53 was required in order to achieve enhanced cytotoxicity in a synergistic fashion [115]. Minodronate in combination with all-trans retinoic acid, thalidomide, or interferonalpha also leads to enhanced growth inhibition in multiple myeloma cells [116]. Combining N-BPs with other inhibitors of protein prenylation is a further approach to enhance the efficiency of N-BPs.

As inhibitors of the 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase (Fig. 2), statins have been shown to exert antitumoural effects on multiple myeloma cells in vitro [117,118]. Schmidmaier and colleagues [119] demonstrated that combined sequential treatment of MM cells with zoledronate and simvastatin synergistically induces apoptosis and reverses cell adhesion-mediated drug resistance, while treatment with zoledronate alone at low and intermediate concentrations does not exert substantial antimyeloma activity. Zoledronate also synergistically interacts with imatinib mesylate (IM) in vitro and in vivo to induce antileukemic activity [120,121]. As a competitive inhibitor of Abl tyrosine kinase, IM is routinely used in the treatment of chronic myelogenous leukemia (CML), where the BCR/ Abl tyrosine kinase is expressed as a consequence of the Philadelphia (Ph) chromosome translocation. Zoledronate inhibits the prenylation of Ras-related

V. Stresing et al. / Cancer Letters 257 (2007) 16–35

proteins downstream of Bcr/Abl, and co-treatment with zoledronate was shown to synergistically augment the antiproliferative effects of IM against Ph+ leukemia cell lines in vitro [120]. In addition, zoledronate was shown to act additively with several other commonly used antileukemic agents in vitro [121]. Some N-BPs (i.e. zoledronate and minodronate) have been shown to synergistically increase the effects of anticancer agents in soft tissue cancers in vitro [9,54,122]. Co-treatment of minodronate with cisplatin or paclitaxel results in enhanced antiproliferative activity on bladder cancer cell lines [9]. In small cell lung cancer, zoledronate increases the effects of paclitaxel, etoposide, cisplatin and irinotecan synergistically, and IM additively [54]. Caraglia and colleagues [122] recently explored a novel strategy to enhance the antitumour action of NBPs, using farnesyl transferase inhibitors (FTI, Fig. 2). FTIs are able to cause multiple effects on cancer cells, including induction of apoptosis, inhibition of cell growth and cell cycle perturbation [123]. Combined treatment of human epidermoid cancer cells with FTI R115777 and zoledronate (or pamidronate) leads to a strong inhibition of cell growth and induction of apoptosis in a synergistic fashion [122]. These studies show that bisphosphonates may act synergistically in combination with a variety of agents, leading to an enhanced cytotoxic activity in many different types of cancer cells. However, it is important to validate the relevance of these in vitro observations also in animal models of cancer. 5.2. In vivo models To date, only a small number of studies have been reported, investigating potential cooperative antitumour effects of N-BPs in vivo (Table 3), mainly focusing on models of skeletal lesions. Hiraga and colleagues [124] examined the effects of the chemotherapeutic agent UFT (tegafur/uracil, 1:4) combined with zoledronate on established bone metastases, using a 4T1 breast cancer animal model. UFT together with zoledronate causes an enhanced reduction of bone metastases compared with UFT alone. In prostate cancer, the combination IM/paclitaxel has been demonstrated to inhibit tumour growth and decrease the incidence of bone metastasis [125]. Co-administration of zoledronate with IM and paclitaxel was shown to further decrease skele-

27

tal tumour burden and lymph node metastasis [126]. In a Ewing sarcoma model, pretreatment with zoledronate was shown to sensitize animals to treatment with paclitaxel and further reduce tumour incidence in animals [49]. Similarly, combined administration of zoledronate and ifosfamide to mice bearing osteosarcoma was demonstrated to result in a synergistic interaction that is more effective in inhibiting local tumour growth and increasing overall survival than either agent alone [127]. Another recent study examined the effects of docetaxel and minodronate on transitional cell carcinoma (TCC) growing in the tibia of athymic nude mice [128]. Administration of minodronate alone leads to a significant regression of skeletal tumours through inhibition of osteoclast activity and subsequent inhibition of malignant bone destruction. The combination docetaxel/minodronate inhibits tumourigenicity in intraossal tumours to a greater extent than either agent alone. The authors conclude that docetaxel and minodronate have complementary cytotoxicities, providing a novel and effective biochemotherapy against osteolytic bone metastasis of human TCC [128]. Regarding the combined effects of N-BPs with cytotoxic drugs in soft tissue tumours, Melisi et al. [129] recently demonstrated the cooperative activity of zoledronate in combination with the COX-2 inhibitor SC-236 and the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor gefitinib, on breast and prostate cancer models in vitro and in xenografted nude mice. The authors had demonstrated previously that inhibition of COX-2 and EGFR causes cooperative antitumour and antiangiogenic activity in human cancer models [130]. The triple combination zoledronate/SC-236/gefitinib was shown to cooperatively induce apoptosis and affect the expression of several proteins involved in cell proliferation and angiogenesis, both in vitro and in vivo [129]. Kuroda et al. [120] demonstrated the synergistic effects of IM and zoledronate on Ph+ leukemias. Co-administration of both agents prolonged the survival of mice inoculated with Ph+ BV173 leukemic cells. The same research group also demonstrated that zoledronate/IM only leads to enhanced survival of mice engrafted with cells from leukemia patients who were imatinibresponders, but not from non-responders because of mutated Bcr/Abl. The authors therefore conclude that this drug combination accelerates the eradication of Ph+ clones, resulting in better prognosis of Ph+ leukemia patients who have not yet acquired

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Table 3 In vivo effects of combined therapy with bisphosphonates and cytotoxic agents Animal model

Agent (dosisa)

N-BP (dosisa)

Type of effect

Ref.

Breast cancer bone metastasis (4T1 cells) Prostate cancer bone metastasis (PC-3MM2 cells)

UFT (0.4 mg/d, oral)

Zol (5 lg i.v., once)

Reduction of bone metastasis

[124]

IM (1 mg/d, oral) + Pac (0.16 mg/wk i.p.)

Zol (1 lg/d s.c.)

Preservation of bone structure

[126]

Ewing sarcoma Bone tumours by human TCC

Pac (12 mg/wk) Doc (0.2 mg/wk i.p.)

Zol (4 lg, 2·/wk) Min (6 lg/wk i.p.)

Osteosarcoma (Rattransplantable)

IFO (0.3 mg i.p., thrice)

Zol (4 lg/wk s.c.)

Prostate cancer (PC3 cells)

SC-236 (0.24 mg 5·/wk i.p) geftinib (3 mg 5·/wk i.p)

Zol (8 mg 2·/wk, i.p.)

Leukemia model (BV173 cells)

IM (2.4 mg/d, oral)

Zol (1.6 lg/k, 3·/wk)

Breast cancer (MDA-MB-436 cells)

Dox (40 lg/wk i.v.)

Zol (2 lg/wk i.p.)

Reduction of tumour incidence Reduction of lymph node metastasis Reduction of tumour incidence Reduction of tumour incidence Growth-reduction of intraossal TCC Prevention of tumour recurrence Improvement of tissue repair Increase of bone formation Inhibition of tumour growth Improvement of overall survival Improvement of overall survival Reduction of extra-osseous breast tumour growth

[49] [128]

[127]

[129]

[120] [132]

Abbreviations: Doc, docetaxel; Dox, doxorubicin; IFO, ifosfamide; IM, imatinib mesylate; Pac, paclitaxel; TCC, transitional cell carcinoma of the urinary tract; UFT, tegafur/uracil. a All doses are calculated per mouse, estimating an average body weight of 20 g/mouse.

mutations [131]. Recently, Ottewell and colleagues [132] have demonstrated the synergistic effects of doxorubicin and zoledronate in a murine MDAMB-436 breast cancer model. Sequential treatment of mice with doxorubicin first, then zoledronate resulted in a synergistic reduction of extra-osseous breast tumour burden, while treatment with each drug alone did not lead to a significant reduction of tumour growth. In summary, the results of these synergistic studies warrant the search for new, highly efficient drug combinations or improved treatment regimens. Many of the drugs described here are already used in the clinical practice, and consequently, these beneficial combinations and treatment schedules might be used in the clinic. 6. Conclusions and future directions There is now ample evidence from preclinical studies that bisphosphonates have the ability to act on tumour cells of various origins [4]. However, there is still an ongoing debate as to what extent these antitumour effects are caused by a direct

action of N-BPs on tumour cells, rather than indirectly through their antiresorptive capacity. Because of their inhibitory effect of osteoclast-mediated bone resorption and the subsequent reduction of bone-derived growth factors, bisphosphonates may render the bone a less favorable microenvironment for tumour cells to attach to and proliferate. In addition, N-BPs may exhibit indirect antitumour activity through antiangiogenic and/or immunomodulatory mechanisms. However, one major shortcoming of most animal studies is the use of high bisphosphonate dosages which by far exceed the clinical dosing regimens given to patients with bone metastases. The clinical relevance of these studies is therefore debatable. It could be argued that the three to five times higher bone turnover in mice would require an equivalently higher N-BP dosage, in order to mimic the clinical situation. However, most animal studies even exceed this high dose, reaching up to 40 times the dosing regimens currently used in the clinic (Table 1). Moreover, the bisphosphonate-dosing regimens that have been used in clinical studies to date have shown no convincing antitumour

V. Stresing et al. / Cancer Letters 257 (2007) 16–35

effects [45,133]. These clinical findings [45,133] are in line with our recent study showing that the treatment of animals bearing breast cancer bone metastases with a single clinical dose of zoledronate (100 lg/kg; calculated to be equivalent to the 4-mg dose given to patients) inhibits bone destruction, but not tumour burden [52]. However, a low dosage of zoledronate, administered to animals on a daily (7 lg/kg) or weekly (50 lg/kg) dosing schedule, not only inhibits bone destruction, but also exhibits meaningful antitumour effects [52]. Thus, these results indicate that a continuous or frequent low-dose therapy with bisphosphonates might affect tumour cells directly, by prolonging the exposure time of bone-residing tumour cells to the drug. In contrast, bisphosphonate therapy with longer dosing intervals only leads to the inhibition of bone resorption. Van der Pluijm et al. [134] also recently reported that a daily preventive low-dose treatment of nude mice with N-BP olpadronate (23 lg/kg) leads to a transient inhibition of skeletal tumour growth in animals bearing MDA-MB-231 breast cancer cells. Similarly, a low dosage of zoledronate on a weekly dosing schedule (30 lg/kg) inhibits not only the formation of osteolytic lesions in HTLV-1 Tax transgenic mice that develop spontaneous leukemia and osteolytic lesions, but also the formation of soft tissue tumours [135]. In the light of these preclinical findings [52,134,135], it is therefore tempting to speculate that the use of a frequent intermittent low-dose bisphosphonate therapy could be an effective way to minimize the development of bone metastases in patients with advanced disease. This therapeutic approach that we propose for bisphosphonates is reminiscent of what is already used for chemotherapy in the clinic. It has been demonstrated that the adjuvant treatment of node-positive breast cancer patients with chemotherapy using a low dosage on short treatment intervals is more effective than escalation of drug dosage levels for residual tumour burden [136]. Given that preclinical findings have shown that the addition of a bisphosphonate to a standard chemotherapy induces additive/synergistic activities (Tables 2 and 3), such combinations using a low-dose intermittent therapy for each agent should be a promising strategy in the treatment of patients with bone metastases. Because of the rapid accumulation of bisphosphonates in bone, it remains, however, unclear whether such combinations could be also effective on extra-skeletal metastases.

29

The development of bisphosphonate analogues with a lower bone mineral affinity could be an effective way to increase the bioavailability of these drugs and to maximize their antitumour potential. For example, we found that a bisphosphonate analogue of risedronate, in which one of the phosphonate groups is substituted by a carboxylate group (NE6790) is as potent as risedronate to inhibit tumour cell invasion in vivo [137]. Moreover, we have preliminary evidence, showing that NE10790 also exhibits direct antitumour activity in an animal model of breast cancer bone metastasis [138]. Such bisphosphonate analogues might represent potential novel treatments in oncology. In addition to using drug combinations or bisphosphonate analogues, the antitumour activity of bisphosphonates may be enhanced by using novel formulations, such as encapsulation in a slow-release matrix like polylactate, liposomes or cyclodextrines. For instance, Zeisberger and colleagues [139] demonstrated that treatment with clodronate encapsulated in liposomes (clodrolip) efficiently depleted tumour-associated macrophages (TAMs) in mouse tumour models resulting in significant inhibition of tumour growth. TAMs play a central role in tumour growth and metastasis by promoting tumour angiogenesis. Clodrolip in combination with an angiogenesis inhibitor consequently showed the strongest effects on tumour-inhibition, whereas free clodronate was not significantly active. Thus, these results provide the rationale for a liposome-encapsulated bisphosphonate therapy in combination with angiogenesis inhibitors as a promising novel strategy for an indirect cancer therapy aimed at the haematopoietic precursor cells that stimulate tumour growth and dissemination. A main limitation of many in vivo studies investigating the anticancer mechanisms of bisphosphonates is the use of immunosuppressed animals, since these models do not take into account the role of the immune system and the possible involvement of bisphosphonates in the stimulation of an immune response. The accumulation of IPP in cancer cells after stimulation with bisphosphonates is possibly the crucial step in the activation of cd T cells, which subsequently triggers the killing of the tumour cells by cd T cells (Fig. 3). Recent studies [21] show that, regardless of the tumour location and the circulating concentrations of bisphosphonates, some cancer cells might not be

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V. Stresing et al. / Cancer Letters 257 (2007) 16–35

able to trigger this immune response, because of the low IPP induction after stimulation with NBP. An N-BP-based immunotherapeutic approach may therefore only be successful in certain types of cancers with a high IPP-induction capacity, while others may gain no additional benefit. However, cells like monocytes and macrophages may also produce IPP upon N-BP-stimulation, and thereby indirectly trigger a T cell-mediated immune response against cancer cells. Immunotherapy may therefore play a major role in the control of malignancies and thus, future studies should be directed to identify the best treatment strategies for different types of cancer. In conclusion, the findings reviewed here reveal at least three novel approaches to fully exploit the antitumour potential of bisphosphonates in the clinical practice: (1) low-dose intermittent bisphosphonate treatment in combination with other drugs, (2) use of phosphono-bisphosphonates or other bisphosphonate analogues with a lower affinity to mineralized bone, and (3) an NBP-based immunotherapeutic approach.

[6]

[7] [8]

[9]

[10]

[11]

[12]

[13]

Acknowledgements F. Daubine´ is a recipient of a fellowship from the French Ministry for Research. P. Cle´zardin received financial support from INSERM (the National Agency for Health and Medical Research), the National Agency for Research (GenHomme, Grant No. 03 L 271), Novartis (Basle, Switzerland) and Procter & Gamble Pharmaceuticals (Cincinnati, OH, USA). H. Mo¨nkko¨nen is a recipient of a postdoctoral fellowship from INSERM and the Department of Pharmaceutics, University of Kuopio.

[14]

[15]

[16]

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