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REVIEW |
1 Department of Experimental Oncology, Experimental Pharmacology Unit National Institute of Tumours ‘Fondaz. G. Pascale’, Via Mariano Semmola, 80131 Naples, Italy
2 Department of Medical Oncology, University Campus Bio-Medico, 00100 Rome, Italy
(Requests for offprints should be addressed to M Caraglia; Email: michele.caraglia{at}fondazionepascale.it)
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Abstract |
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 Top Abstract IntroductionBiochemical pathways as...The isoprenylation processSuggested intracellular...Clinical evidence of anti...ConclusionsReferences |
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Introduction |
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TopAbstractIntroductionBiochemical pathways as...The isoprenylation processSuggested intracellular...Clinical evidence of anti...ConclusionsReferences |
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The high prevalence of bone metastases in patients with advanced metastatic disease contributes substantially to the burden of disease. Bone metastases are associated with considerable skeletal morbidity — including severe bone pain that may require strong narcotics or palliative radiation therapy — pathological fracture, spinal cord or nerve root compression, and hypercalcaemia of malignancy (HCM), which can substantially reduce quality of life. Across all tumour types, patients with breast cancer have the highest incidence of skeletal complications (Berenson et al. 1998, Lipton et al. 2000, Rosen et al. 2004b, Saad et al. 2004). After over 2 years of follow-up, nearly 70% of patients treated with placebo had more than one skeletal complication, and approximately 50% experienced a pathological fracture (Lipton et al. 2000). Patients with multiple myeloma, prostate cancer, lung cancer or other solid tumours are also at high risk for skeletal complications. The most common events in all tumour types are radiation to bone and pathological fracture. These complications result from excessive bone metabolism, principally bone resorption which characterizes malignant bone lesions and leads to severe bone pain. Therefore, there is a great need for therapies that effectively inhibit bone resorption, thereby reducing the risk of skeletal complications. Consequently, bisphosphonates (BPs) have become the standard treatment for malignant bone disease. BPs effectively inhibit bone resorption, have been shown to significantly reduce the incidence of skeletal complications and have analgesic effects on bone pain (Ross et al. 2003).
Traditional approaches for treating patients with bone metastases include standard anti-neoplastic therapies (chemotherapy or biological therapies), which may be administered in conjunction with additional supportive or palliative therapies. Severe bone pain is treated with radiotherapy and/or radionuclides, and many patients also receive systemic analgesic treatment with non-steroidal anti-inflammatory drugs or opioids. Radiotherapy is also used to stabilize bone lesions and may prevent impending fractures. Orthopaedic surgery is used to treat existing fractures or to prevent impending fractures or spinal cord compression. In addition to these strictly palliative interventions, BPs have emerged in recent years as a highly effective therapeutic option for the prevention of skeletal complications secondary to bone metastases. BPs bind preferentially to bone at sites of active bone metabolism, are released from the bone matrix during bone resorption and potently inhibit osteoclast activity and survival, thereby reducing osteoclastmediated bone resorption (Fleisch 2002). Newer nitrogen-containing bisphosphonates (NBPs) — such as zoledronic acid (ZOL), pamidronate (PAM) and ibandronate (IBA) — have a unique mechanism of action and greater clinical activity than first-generation BPs such as etidronate and clodronate (Green 2003). These newer agents are orders of magnitude more potent than the first-generation compounds. Consequently, they can inhibit bone resorption at micromolar concentrations.
BPs inhibit osteoclast activity at multiple levels; they prevent differentiation of macrophages into osteoclasts, block the activity of mature osteoclasts and induce osteoclast apoptosis (Rodan 1998, Rogers et al. 2000). The exact molecular mechanisms of action of BPs are only partially understood and appear to differ among different families of BPs (Fleisch 1998, Rodan 1998). Non-nitrogen-containing BPs (e.g. clodronate and etidronate) can be incorporated into non-hydrolyzable ATP analogues, which accumulate intracellularly and thereby suppress ATP-dependent enzymes (Rogers et al. 1996a). NBPs inhibit critical enzymes of the mevalonate pathway, in particular farnesyl diphosphate synthase, required for the synthesis of farnesyl diphosphate and geranylgeranyl diphosphate, and thereby suppress prenylation of small GTPases essential for many cellular functions (Luckman et al. 1998, van Beek et al. 1999b, Bergstrom et al. 2000, Dunford et al. 2001).
Clinical and experimental evidence indicates that NBPs suppress the progression of bone metastases, and recent observations suggest that this effect may be independent of the inhibition of bone resorption (Neville-Webbe et al. 2002, Green 2003). Tumour progression and metastasis formation are critically dependent on tumour angiogenesis (Carmeliet & Jain 2000). Anti-angiogenic treatments suppress tumour progression in animal models, and many anti-angiogenic substances are currently being tested in clinical trials for their therapeutic efficacy against human cancer (Carmeliet 2003). Recent evidence indicates that zoledronate possesses anti-angiogenic activities as discussed below.
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Biochemical pathways as molecular targets of NBPs: the mevalonate pathway |
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TopAbstractIntroductionBiochemical pathways as...The isoprenylation processSuggested intracellular...Clinical evidence of anti...ConclusionsReferences |
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In human cells, isoprenoids are derived from the mevalonate pathway that starts from reaction catalyzed by the 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase (the rate-limiting reaction in cholesterol biosynthesis) which catalyzes the conversion of HMGCoA to mevalonic acid. The pathway triggered by this reaction can lead to the synthesis of a key isoprenoid molecule: the farnesyl-pyrophosphate (FPP) whose formation is catalyzed by the farnesylpyrophosphate synthase (FPPS) (Soma et al. 1992). FPP can be: converted by a series of reactions into cholesterol; or transferred on target cellular proteins as FPP itself (reaction catalyzed by farnesyltransferase); or firstly converted into geranylgeranyl-pyrophosphate and then transferred on cellular proteins by type I or type II geranylgeranyltransferase.
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The isoprenylation process |
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TopAbstractIntroductionBiochemical pathways as...The isoprenylation processSuggested intracellular...Clinical evidence of anti...ConclusionsReferences |
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- and ß-subunits with combined molecular masses ranging from 91 to 98 kDa. The -subunits of FTase and GGTase-I are the same, and the ß-subunits differ. The ß-subunits of the three enzymes are homologous to the -subunits and to each other. The isoprenoid groups become linked to polypeptidic cysteines through thioether (C–S–C) bonds. Conversion of the protein–cysteine acceptor site to protein–serine in oncogenic H-Ras prevents prenylation and abolishes its malignant transforming ability (Lowy & Willumsen 1993). FTase and GGTase-I catalyze the prenylation of substrates with a carboxy-terminal tetrapeptide sequence called a CA1A2X box, where C refers to cysteine, A refers to an aliphatic residue and X typically refers to methionine, serine, alanine or glutamine for FTase or to leucine for GGTase-I. Following prenylation of physiological substrates, the terminal three residues (A1A2X) are subsequently removed by a CA1A2X endoprotease and the carboxyl group of the terminal cysteine is methyl esterified by a methyltransferase (Zhang & Casey 1996). Protein GGTase-II, or Rab GGTase, catalyzes the geranylgeranylation of Rab proteins that terminate in CC or CXC sequences. Rab proteins ending with CXC residues are methyl esterified; those ending with CC are not. FTase and GGTase-I can catalyze the prenylation of tetrapeptides, polypeptides and proteins containing appropriate CA1A2X box sequences. GGTase-II, in contrast, cannot catalyze the prenylation of these peptides; it uses a Rab–Rab escort protein heterodimer as substrate (Zhang & Casey 1996). There are a few exceptions to the substrate-specificity rules for FTase and GGTase-I noted above. K-RasB, which has a classical FTase CA1A2X box (CVIM), is a substrate for FTase. Following inhibition of cellular FTase, K-RasB becomes a substrate for geranylgeranylation by GGTase-I (Gibbs 2001, Yokayama & Gelb 2001). The latter reaction is made possible by an upstream polybasic sequence that alters GGTase-I substrate specificity. Furthermore, RhoB, which contains a GGTase-I CA1A2X box (CKVL), is found in both farnesylated and geranylgeranylated forms in cells. This is due to the ability of GGTase-I to both geranylgeranylate and farnesylate this substrate (Armstrong et al. 1995). It appears that upstream sequences (as yet uncharacterized) are responsible for this altered substrate specificity. Moreover, Cdc42, which contains a carboxyterminal CCIF sequence, undergoes geranylgeranylation. Ordinarily GGTase-I substrates contain leucine in the X position of the CA1A2X box, but Cdc42 represents an exception to the leucine rule (Roskoski 2003). All three prenyltransferases require Zn2+, and FTase and GGTase-II require Mg2+ for activity (Huang et al. 1997, Hightower et al. 1998, Spence & Casey 2001, Terry et al. 2001, Urano et al. 2001, Yokayama & Gelb 2001). Both protein geranylgeranylation and farnesylation are followed by the cleavage of the terminal tripeptide A1A2X, catalyzed by a specific peptidase, and by the subsequent methylation of the terminal cysteine catalyzed by a methyltransferase. Finally, the protein is ready to be translocated on the cellular membranes to receive extra- or intracellular signals. After methylation, a palmitoylation on the -SH group of the penultimate cysteine residue can occur. This last reaction is reversible and occurs only for Ras proteins with a cysteine residue upstream of the CAAX motif (namely H-Ras, N-Ras and K-Ras4A), whereas the other CAAX-triggered events are irreversible (Clarke et al. 1988, Hancock et al. 1991, Zhang & Casey 1996) (for a summary see Fig. 1
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Suggested intracellular molecular targets of NBPs |
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TopAbstractIntroductionBiochemical pathways as...The isoprenylation processSuggested intracellular...Clinical evidence of anti...ConclusionsReferences |
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Many solid tumours cause hypercalcaemic bone destruction and the primary cause of this is often due to release of parathyroid hormone-related peptide (PTHrP). This may be released by the primary tumour, or by metatases, and can cause intense general or local bone destruction. Moreover, transforming growth factor (TGF)-ß, one of the most abundant of the bone-derived factors, promotes increased production of PTHrP by tumour cells, establishing a ‘vicious cycle’ leading to progressive tumour growth and bone destruction. BPs interrupt this cycle by inhibiting osteoclasts, in part by inducing osteoclast apoptosis (Mundy et al. 2001).
However, the exact molecular target of NBPs is still unknown and its identification could be useful in potentiating the beneficial effects of these drugs. Several isoprenylated molecules are emerging as potential targets of NBPs and they could be differently implicated in the biological effects induced by these agents. In order to be clear on the identification of the emerging molecular mechanisms responsible for the different biological effects (antiproliferative, anti-invasive and anti-angiogenic), each effect will be discussed separately.
Anti-proliferative effect: apoptosis and cell cycle disruption
Taking into account the relative importance of ras in regulating cell proliferation of several tumours both in vitro and in vivo, attention has been focused on ras in order to explain the direct anti-proliferative effects of NBPs. Two mechanisms of NBP-induced tumour growth inhibition have been described: cell cycle disruption and apoptosis. In this regard, it has recently been demonstrated in vitro that NBPs, such as PAM and ZOL, induce apoptosis and growth inhibition in human epidermoid cancer cells, together with depression of ras signalling and of Erk and Akt survival pathways. These effects occurred together with poly (ADP ribose) polymerase (PARP) fragmentation and the activation of caspase 3. Moreover, the latter seemed to be essential for apoptosis induced by NBPs in this experimental model. The synthesis of isoprenoids appeared largely responsible for the biological and biochemical effects of NBPs since the addition of farnesol (FOH), which restores farnesylation, to tumour cells completely antagonized apoptosis and the inhibition of ras activity in tumour cells exposed to NBPs. These data suggest that the activity of NBPs could be due to the inactivation of the farnesylpyrophosphate synthase activity (Caraglia et al. 2004). Moreover, the effects of ZOL on growth inhibition and apoptosis seemed to be p53-independent (Kuroda et al. 2004). In fact, Kuroda et al. have demonstrated that 40 µM ZOL induced about 40% apoptosis in leukaemia and colon cancer cells. The effect on growth inhibition was not dependent on p53 function since p53-defective colon cancer HCT116/E16 cells were equally as sensitive to ZOL as the parental cells. In these experimental conditions, ZOL decreased rap-1A prenylation and Erk activity, but had no effects on the expression of cyclin-dependent kinase inhibitors p27 and p21, and also increased the expression of M-phase cyclins. These results suggest that ZOL induced p53-independent growth inhibition and apoptosis in these experimental systems. In contrast to the results of Caraglia et al. (2004) apoptosis induced by NBPs could also be due to the inhibition of ras geranylgeranylation instead of farnesylation as recently demonstrated by Senaratne et al. (2002). These conclusions are further supported by the findings of Coxon et al. (2004) who described apoptotic effects after 48 h of exposure to 100 µM ZOL on prostate adenocarcinoma DU145 and PC3 cells. Apoptosis was completely antagonized by both the pan-caspase inhibitor and by the addition of geranyl-geranol (GGOH), which restores geranylgeranylation, but not by FOH. Similar effects on apoptosis induction were also recorded after FTI manumycin A addition; this was, however, aspecific and also acted on GGTase. In this report, the inhibition of Rho A, a geranylgeranylated protein, through the use of C3 exoenzyme, was not able to induce apoptosis. Therefore, the authors failed to detect a putative molecular target of NBPs and it could only be suggested that a ras isoform or another GTP-binding protein that can be geranylgeranylated was involved. On the other hand, other data exclude the involvement of ras in the anti-proliferative effects exerted by ZOL on human prostate adenocarcinoma cells. In fact, Nogawa et al. (2005) found that the amount of membrane-anchored ras (the active fraction of ras) was clearly independent of ZOL-mediated growth inhibition of prostate cancer cell lines and concluded that geranylgeranylation of a still unknown substrate could be a therapeutic target in this experimental model. Moreover, it was also shown that PAM, alendronate and risedronate were all able to induce apoptosis in osteoclasts through the caspase cleavage of mammalian sterile 20-like kinase 1 (Mst1) to form the active 34 kDa species associated with apoptosis. Moreover, these effects seemed to be independent on the blockade of geranylgeranylation (Reszka et al. 1999). Both incandronate and etidronate accelerate phosphate-primed mineralization of a murine calvaria-derived osteoblastic cell line through the Erk1/2-Cbfa1 signalling pathway again in a ras-independent manner (Fujita et al. 2001). In this report, a differential involvement of Erk1/2 and Akt-dependent pathways was also described since risedronate suppressed the phosphorylation of ERK 1/2, affected the intracellular distribution of Bcl-xL and facilitated dephosphorylation of Bad at Ser112 (an ERK phosphorylation site), but not at Ser136 (an Akt phosphorylation site). All of these apoptosis-related changes induced by risedronate were strongly suppressed by cytochalasin B, an inhibitor of actin filament polymerization, thus excluding ras involvement but not suggesting an alternative substrate (Fujita et al. 2005). Moreover, differential biochemical effects within the different NBPs can not be excluded. In fact, it is known that the anti-resorptive effects of PAM are not completely inhibited by the addition of GGOH which, in turn, is able to antagonize completely the effects of alendronate (van Beek et al. 2003).
Based on the evidence that NBPs act as inhibitors of geranylgeranylation, a later-generation NBP NE10790 was developed with the specific ability to inhibit the activity of Rab GGTase but with no activity against either FTase or GGTase I (Coxon et al. 2001). NE10790 was able to inhibit bone resorption without affecting osteoclast number and causing the formation of intracellular vacuoles and protrusions of the basolateral membrane, thus affecting Rab-mediated intracellular trafficking (Coxon et al. 2001). Therefore, it is possible to design NBPs with selective activity against GTP-binding proteins different from ras and rho.
Another way to induce cell growth inhibition is cell cycle perturbation. In this regard, it was reported that ZOL at concentrations higher than 100 µM induced 75% growth inhibition after 4 days of treatment on both androgen-dependent LnCaP and androgen-independent PC3 prostate cancer cell lines (Corey et al. 2003). In these experimental conditions G1 accumulation was found, even at only 2 days from the beginning of the treatment. The same authors reported the anti-cancer effects of ZOL on bone PC3 and LnCaP xenografts and the effect was paralleled by a significant reduction in serum prostate-specific antigen (PSA). The ability of ZOL to induce growth inhibition in cancer cells has also been studied in correlation with the reduced expression of metallo-proteinase (MMP)-2 and MMP-9 in PC3 cells, but not LnCaP cells. The effects of NBPs on cell cycle inhibitors was further confirmed by Reszka et al. (2001) who described the effects of alendronate and risedronate on normal human epidermal keratinocytes (NHEKs). Alendronate and risedronate induced growth inhibition without apoptosis and with S-phase accumulation in NHEKs. These effects were paralleled by p21 and p27 increased expression and consequent decreased phosphorylation of Rb likely due to the inhibition of geranylgeranylation.
In summary, these findings suggest again that the real targets of NBPs, responsible for growth inhibition, are still undiscovered and that their identification requires further investigations.
Anti-invasive effects
It has been reported that ZOL is also able to inhibit tumour cell invasiveness of breast and prostate cancer at 1 µM concentrations; this makes it 150-fold more potent than other NBPs such as risedronate and PAM, and very different from non-nitrogen BPs such as clodronate (Boissier et al. 2000). At these concentrations, ZOL does not induce apoptosis and inhibits the in vitro activity of several MMPs. The authors suggest that this inhibition was due not to a decreased synthesis of the enzymes, but to the steric interaction between the bone hook of NBPs and the active site of the proteins, since only at higher concentrations were NBPs able to reduce the secretion of these enzymes. However, Montague et al. (2004) have reported that ZOL and PAM reduce prostate cancer PC3 invasion on matrigel chambers (also at a concentration of 5 µM ZOL) and inhibit the binding of PC3 to the marrow stroma. Finally, ZOL was also able to inhibit PC3 colony formation on marrow stroma at the optimal concentration of 10 µM. All these effects were paralleled by the inhibition of MMP7 secretion and tissue inhibitor of matrix metalloproteinase (TIMP)-2 expression. In these experimental conditions, decreasing vascular endothelial growth factor (VEGF) and granulocyte monocyte colony stimulating factor expression was also recorded. Denoyelle et al. (2003), in agreement with previous studies (Fromigue et al. 2000, Hiraga et al. 2001, Jagdev et al. 2001), have also shown that ZOL inhibits breast cancer cell proliferation, but only at high concentrations (4100 µM) that are certainly higher than those obtained in vivo. The effect of ZOL has also been studied on breast MDA-MB- 231 cell invasion. After an 18 h incubation time, ZOL, at low concentrations (from 100 nm), conferred potent anti-invasive properties on MDA-MB-231 cells (62% decrease at 1 µM). As ZOL did not induce apoptosis at these concentrations, the possibility that ZOL interfered with invasion by inducing cell death was excluded. This is also in agreement with the observations of Boissier et al. (2000). The same authors have shown that it does not involve proteases involved in tumour invasion by inducing the degradation of the extracellular matrix (ECM). Indeed, neither MMP secretion nor u-PA (urokinase-plasminogen activator) expression was modified at concentrations that inhibit cell invasion. Reduction of the secretion of both MMP-2 and MMP-9 (Boissier et al. 2000) and u-PA expression in MDA-MB-231 cells required much higher concentrations. In contrast, u-PA receptors expressed on the cell surface of MDA-MB-231 cells were dramatically reduced by ZOL at low concentrations. u-PA receptor is a ligand for vitronectin, which is a common protein in the mature bone microenvironment (Cooper et al. 2002). Consequently, the decrease of u-PA receptor by ZOL could contribute to the previously reported prevention of breast cancer cell attachment on to bone matrices (van der Pluijm et al. 1996, Boissier et al. 1997). In this study, it was demonstrated that GGOH, which restores geranylgeranylation, but not FOH, which restores farnesylation, reversed the effect of ZOL, suggesting that the inhibition of protein(s) geranylgeranylation rather than farnesylation seems to account for ZOL anti-invasive action. To test this hypothesis further, the effect of FTI-277 and GGTI-298 (which potently and selectively inhibit FTase and GGTase respectively), was compared with the action of ZOL on breast cancer cell invasiveness (Lerner et al. 1995, Vogt et al. 1996). The incubation of MDA-MB-231 cells with GGTI-298 mimicked the anti-invasive effect of ZOL, whereas FTI-277 did not. Thus, inhibition of protein geranylgeranylation seems to be important in explaining the anti-invasive action of ZOL. This effect was also mimicked by C3 exoenzyme, which is a specific inhibitor of RhoA, but not other Rho subfamily members, Rac and Cdc42 (Boquet 1999). Therefore, it was suggested that the inhibition of cell invasion by ZOL could be related to the inhibition of RhoA cell signalling. This was also supported by the observation that ZOL at low concentrations prevents the translocation of RhoA from cytoplasm to the cell membrane. In contrast to the effect of ZOL on cell invasion, the inhibition of cell proliferation seemed to be independent of RhoA inactivation because at the concentration for which RhoA, but not ras, was inhibited, cell proliferation and apoptosis were unaltered. Denoyelle et al. (2003) reported that ZOL also inhibited the chemotactic effect induced by the chemokine SDF-1 on MDA-MB-231 cells. This observation constitutes an important addition to the mechanistic understanding of how NBPs, given in the adjuvant setting, could prevent the development of bone metastases as shown by two clinical trials (Diel et al. 1998, Powles et al. 2002). Similar data were obtained with aledronate on the invasiveness and migration of both ovarian and prostate cancer cells (Sawada et al. 2002, Virtanen et al. 2002). Sawada et al. (2002) have also reported that alendronate inhibited lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of RhoA. These effects were again antagonized completely by GGOH and partially by FOH. On the other hand, Virtanen et al. (2002) have demonstrated that alendronate was able to decrease the migration and invasion of human prostate cancer cells and these effects were completely antagonized by both GGOH and FOH. Possible explanations of the discrepancy of this study with all the other reports could be the following: (a) compensatory conversion of some FOH to geranylgeranyl by farnesyl; (b) since rho can be activated by ras, Ras-activation induced by FOH could still stimulate cell spreading and actin filament assembly through the activation of Rho.
Taken together these data prevent conclusive remarks on the molecular targets of NBPs being given. However, considering the results from the literature it can be suggested that inhibition of the isoprenylation of intracellular proteins could be the mechanism of action of NBPs. Moreover, ras seems to be involved in the induction of apoptosis while rho-A is involved in the regulation of cell invasion (for a summary see Fig. 2).
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Both in vitro and in vivo studies have further demonstrated that NBPs have anti-angiogenic effects. In vitro assays with human umbilical vein endothelial cells (HUVECs) have shown that ZOL dose-dependently inhibited the proliferation of HUVECs induced by fetal calf serum and basic fibroblast growth factor (bFGF), and these findings have been confirmed in vivo.
Systemic administration of ZOL to mice resulted in potent inhibition of angiogenesis induced by s.c. implants impregnated with bFGF, with a dose of 3 µg/kg producing a 50% efficacy (ED50) (Wood et al. 2002). It has also been reported that ZOL can reduce bone-tumour-associated angiogenesis in the murine 5T2 myeloma model (Croucher et al. 2003).
In another series of experiments, ZOL, as well as IBA, risedronate and clodronate, inhibited the formation of capillary-like tubules by HUVECs in vitro. In vivo, ZOL and IBA, but not clodronate, decreased revascularization (as measured by vessel area) of the ventral prostate gland in castrated rats treated with testosterone (Fournier et al. 2002).
The inhibitory effect of NBPs on endothelial cell adhesion and migration appears to be mediated, at least in part, by modulation of integrins (e.g. vß3 and vß5) that are involved in angiogenesis (Bonjean et al. 2001, Bezzi et al. 2003). Interestingly, vß3 integrin is also required for osteoclasts to adhere tightly to the bone and form resorption lacunae during active bone resorption, and vß3 expression confers on tumour cells a greater propensity to metastasize to bone (Pécheur et al. 2002). In fact, a small molecule inhibitor of vß3 was recently shown to prevent effectively the metastasis of MDA-MB-435 breast cancer cells to bone (Harms & Welch 2003).
Therefore, effects on vß3 could be pleiotropic on both bone resorption and tumour metastasis. In addition, it has recently been reported that ZOL decreases the survival of HUVECs by sensitizing them to tumour necrosis factor-induced programmed cell death. ZOL also appears to modulate serum levels of pro-angiogenic growth factors such as VEGF and bFGF in cancer patients (Santini et al. 2003), as previously demonstrated also for the parent compound PAM (Santini et al. 2002). These studies suggest a variety of potential mechanisms to account for the observed anti-angiogenic effects of NBPs (for a summary see Fig. 2
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Clinical evidence of anti-resorptive and anti-cancer activity of NBPs |
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TopAbstractIntroductionBiochemical pathways as...The isoprenylation processSuggested intracellular...Clinical evidence of anti...ConclusionsReferences |
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Regardless of the cancer type, ZOL resulted in a statistically significant lower cumulative incidence of skeletal-related event (SREs) compared with PAM (in patients with breast cancer) and placebo (in patients with prostate cancer or other solid tumours). Moreover, the overall safety profile of ZOL was comparable with those of other i.v. BPs (Major et al. 2004).
The clinical benefits of BP therapy have been evaluated in many clinical trials designed to capture data on skeletal complications. The majority of these trials used a composite end point defined as a SRE or bone event, which generally includes events such as pathological fracture, radiation to bone, surgery to bone, spinal cord compression, and HCM. Such composite end points capture data on all clinically relevant events and are more likely to detect therapeutic benefits when treatment effects and disease morbidity are multifaceted (Johnson et al. 2003).
Using a composite definition of skeletal events, it is possible to assess treatment effect using a variety of outcome analyses. First-event descriptors such as proportion of patients with 
1 SRE or time to first SRE are objective and conservative end points that provide readily assessable estimations of treatment effect. Of these, the US Food and Drug Administration has suggested that time to first event is the preferred end point because it also accounts for the patient’s time on the study (Williams et al. 2004).
However, first-event analyses only capture information about the first event and ignore data on all subsequent events that occur in any given patient. Skeletal morbidity rates (SMRs) or skeletal morbidity period rates (SMPRs) assess the number of events that occur during a designated time period (e.g. events per year). These analyses account for the occurrence of multiple skeletal events but assume that these events occur at a constant rate. However, clinical evidence suggests that patients with bone metastases exhibit considerable variation in both the number of skeletal events they experience and the rate at which these events occur (Major et al. 2004).
Moreover, skeletal events do not demonstrate random distribution but often occur in clusters. Therefore, analyses that assume a linear event rate tend to overestimate the differences between study groups and may unduly overestimate treatment effects (Major & Cook 2002).
Regression analyses such as a Poisson analysis or the Andersen–Gill multiple event analysis are able to model all events, as well as the time between events, and are able to account for inter- and intra-patient variations in event rates (Andersen & Gill 1982).
However, Poisson analyses that do not account for non-constant event rates are subject to the same limitations as those of other analyses, such as analyses using SMR, that do not account for variability in event rate. Therefore, multiple event analysis provides a statistically robust and comprehensive assessment of skeletal morbidity throughout the entire length of follow-up. Andersen–Gill multiple event analysis calculates a hazard ratio (HR) which indicates the extent to which the risk of skeletal events is affected by one specific treatment relative to another. A hazard ratio <1 indicates a favourable treatment effect. Recently, non-parametric methods for multiple event analysis have been described (Cook & Lawless 1996, Ghosh & Lin 2000).
These models calculate the cumulative incidence of skeletal complications and allow for right-censored data, thus accounting for death or study discontinuation for other reasons. Together, all these statistical analyses provide both conservative and comprehensive assessments of the clinical benefit of BPs in patients with bone metastases.
NBPs in breast cancer
ZOL (4 mg in 15-min infusions every 4 weeks for 1 year) was also recently compared with placebo in 227 Japanese women with bone metastases from breast cancer (see Kohno et al. (2004) and Theriault et al. (1999)). In that trial, the primary end point was the SRE rate ratio adjusted for history of pathological fractures before study entry, which showed a significant 39% lower rate of SREs in the ZOL group (ratio=0.61; P=0.027). In addition, secondary efficacy analyses showed that ZOL produced a significantly lower percentage of patients with an SRE (31% versus 52% for placebo; P=0.001) and significantly longer time to first SRE (median was not reached in ZOL group versus 360 days for placebo; P=0.004) than placebo. Multiple event analysis demonstrated a 44% lower risk of developing an SRE (HR=0.56; P=0.009) in the ZOL group. It is noteworthy that the magnitude of the clinical benefit of ZOL observed in that trial appears to be greater than that achieved with PAM or IBA in similar patient populations after 1 year of treatment (Hortobágyi et al. 1996, Theriault et al. 1999). Similar to the PAM trials, patients enrolled in this trial had predominantly osteolytic lesions. ZOL was well tolerated; the adverse events that occurred more often with ZOL than with placebo included acute-phase, infusion-related symptoms of pyrexia (55% versus 33% for placebo), fatigue (44.5% versus 31.9% for placebo) and arthralgia (21.1% versus 15.9% for placebo). Only 1 of 114 patients experienced an elevated serum creatinine level with ZOL treatment in that study (Table 1).
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). In addition, among patients with predominantly osteolytic lesions, ZOL has been shown, by Andersen–Gill analysis, to result in a 30% significantly lower risk of developing SREs compared with PAM (P=0.010). Therefore, based on the comprehensive assessment of skeletal morbidity provided by two independent multiple event analyses, ZOL appears to be superior to PAM in patients with breast cancer. Based on this trial, ZOL has received broad international approval for the treatment of patients with bone metastases from breast cancer and is becoming the new standard of care worldwide (Rosen et al. 2004b).
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In contrast to clodronate and PAM, ZOL (4 mg via a 15-min infusion every 3 weeks) has demonstrated statistically significant reductions in the incidence of SREs and sustained palliation of bone pain over 2 years in patients with bone metastases from hormone-resistant prostate cancer (HRPC). The results of this multicentre, randomized, placebo-controlled trial enrolling 643 patients were first reported at 15 months and then after 2 years of treatment (Zekri et al. 2001, Saad et al. 2004).
The primary end point was the percentage of patients with >1 SRE — defined as pathological fracture, radiation or surgery to bone, spinal cord compression, HCM, or change of therapy to treat bone pain. Secondary end points included time to first SRE, SMR, Andersen–Gill multiple event analysis, and Bone pain intensity (BPI) score. After 2 years, treatment with ZOL resulted in a significantly lower percentage of patients with >1 SRE (38% versus 49% for placebo; P=0.028) and consistently lower incidences of all types of SREs, particularly fractures (Saad et al. 2003) (Table 1).
ZOL also produced a 36% significantly lower risk of developing a skeletal complication, as compared with placebo by multiple event analysis (HR=0.640; P=0.002) (Zekri et al. 2001) (Table 1).
Recently, Ernst and colleagues (2003) reported the results of a randomized, double-blind, controlled trial comparing the incidence of palliative response in HRPC treated with mitoxantrone and prednisone (MP) plus clodronate, with that of patients treated with MP plus placebo. They failed to demonstrate a significant difference between the arm groups but suggested a possible benefit of adding clodronate in patients with more severe pain.
NBPs in other solid cancers
To date, ZOL is the only BP to be evaluated for the prevention of skeletal complications in patients with bone metastases secondary to solid tumours other than breast or prostate cancer. In the first trial, 773 patients with bone metastases from non-small cell lung cancer (NSCLC) or other advanced-stage solid tumours were randomized to receive either ZOL (4 mg via a 15-min infusion) or placebo every 3 weeks for 21 months (Rosen et al. 2004a). That trial enrolled a diverse patient population composed of patients with NSCLC (49% of patients) and more than 20 other tumour types including renal cell carcinoma (RCC), colorectal cancer, small cell lung cancer and bladder cancer. However, this was a poor-prognosis group of patients with a median survival of only 6 months, and patients received a median of only four infusions of ZOL. Nevertheless, Andersen–Gill multiple event analysis demonstrated that treatment with ZOL resulted in a 31% significantly lower risk of developing an SRE compared with placebo (HR=0.693; P=0.003), and ZOL produced a significantly longer median time to first SRE (236 days versus 155 days for placebo; P=0.009) (Table 1). A long-term subset analysis of 46 patients with RCC enrolled in that trial has also been reported (Lipton et al. 2004), showing that patients with bone metastases secondary to advanced RCC are at extremely high risk for skeletal complications. Among patients randomized to placebo, 79% had >1 SRE over 21 months of follow-up. Moreover, ZOL provided highly significant clinical benefits in this subset (Table 1). For example, patients treated with 4mg ZOL had a significantly lower SRE incidence of 41% (P=0.011) and longer time to onset of SREs (by approximately 1 year) than patients treated with placebo (median 424 days versus 72 days for placebo; P=0.007). In addition, Andersen–Gill multiple event analysis showed that ZOL produced a 58% lower risk for SREs (HR=0.418; P=0.010). Even more noteworthy is the observation that treatment with ZOL resulted in greater bone lesion response and a significantly longer time to progression of bone lesions by approximately 6 months (median 256 days versus 89 days for placebo; P=0.014). ZOL was well tolerated in patients with RCC; the most common adverse events reported by patients for both 4mg ZOL and placebo included bone pain, nausea, vomiting, anaemia and fatigue. There was no significant difference between treatment groups in the incidence of renal-related adverse events (Table 1). These results indicate that the predominantly osteolytic bone metastases associated with RCC are clinically aggressive, and these patients are at high risk for skeletal complications, but this risk can be significantly reduced with ZOL.
The clinical results based on the use of either clodronate or IBA are summarized in Table 1 and indicate that they are less promising than ZOL.
Most of the effects on bone are mediated by endocrine changes, either induction of an early menopause by chemotherapy and ovarian ablation, or further suppression of post-menopausal circulating oestrogens by aromatase inhibitors. Several studies have reported that cancer treatment-induced bone loss (CTIBL) can be prevented with BP treatment (Saarto et al. 1997, Powles et al. 1998). The Z-FAST study is the first trial designed to prevent, with ZOL, the bone loss that occurs with aromatase inhibitors in the typical post-menopausal setting. In this study, patients treated with adjuvant letrozole are randomized to either immediate treatment with ZOL (4 mg every 6 months) or to a delayed strategy. Preliminary 12-month bone mineral density (BMD) data have showed that upfront ZOL preserves bone density. However, further follow-up is required to determine the clinical importance of this over a wait-and-see policy (Brufsky et al. 2005).
Predictive value of bone resorption and formation markers in bone metastatic cancer patients receiving the BP ZOL
Coleman et al. (2005) have recently investigated the correlation between bone metabolism and clinical outcome during BP therapy. They analysed urinary measurements of N-telopeptide (Ntx) obtained in 1824 BP-treated patients (1462 multiple cancer types with ZOL and 362 with PAM) and estimated the correlation between this bone resorption marker and the relative risks for negative clinical outcomes. Interestingly, Ntx levels correlated with risk of skeletal complications and disease progression and, furthermore, high Ntx levels in each solid tumour category were associated with a 4- to 6-fold increased risk of death on study. This impressive study highlights the role of the bone resorption marker Ntx in providing correct prognostic information in patients with bone metastases receiving BPs. This could lead to the selection of cancer patients who might benefit most from therapy with BPs by evaluating urine or serum markers that predict who is at highest risk for skeletal complications and disease progression.
Translation of the results derived from pre-clinical studies in the treatment of human neoplasms
A series of pre-clinical findings suggest that NBPs have direct anti-tumour effects acting on different phases of tumour growth and progression. Moreover, the molecular targets and mechanisms of these effects are becoming clear. Clinical studies are confirming the activity of NBPs in preventing not only SREs but also skeletal metastases occurrence. The latter in vivo effect suggests a putative anti-invasive potential of NBPs. However, due to the intrinsic limitations of current NBPs, further efforts are required in order to allow the clinical translation of experimental results recorded to date and to increase the anti-cancer activity of these drugs. Two possibilities are the improvement of the pharmacokinetic profile and the design of rationale-based drug combinations.
Improvement of the pharmacokinetic profile
One of the most important limits of NBPs, which makes the direct anti-cancer activity difficult to demonstrate in vivo, is their pharmacokinetic profile. This issue is demonstrated by pharmacological studies performed on different NBPs. In fact, studies on ZOL pharmacokinetics demonstrate that, after intravenous administration (4 mg over 15 min), an abrupt increase of its concentration in peripheral blood is recorded, as shown by estimations of the early distribution and elimination of the drug, which results in plasma half-lives of the drug of about 15 min (t1/2) and of 105 min (t1/2ß) respectively. The maximum plasma concentration (Cmax) of ZOL is about 1 µM; that is 10- to 100- fold less than that required in in vitro studies to induce apoptosis and growth inhibition in tumour cell lines, while the concentrations required for anti-invasive effects are in the range of those achieved after in vivo administration. Moreover, approximately 55% of the initially administered dose of the drug is retained in the skeleton and is slowly released back into circulation, resulting in a terminal elimination half-life (t1/2
) of about 7 days (Chen et al. 2002, Skerjanec et al. 2003). Other studies performed on alendronate demonstrate that NBP concentration in non-calcified tissues declines rapidly at 1 h (5% of the initial concentration). On the other hand, its concentration in the bone continuously increases, reaching its peak at 1 h, demonstrating that a significant redistribution of the drug from non-calcified tissues to bone occurs. The drug is retained in bone tissue for a long time and is slowly released into plasma, with a terminal half-life of about 200 days (Lin 1996). Similar data were obtained with IBA and ZOL (Chen et al. 2002, Barrett et al. 2004) demonstrating that long-lasting accumulation in bone is a common feature of NBPs. The rapid redistribution of NBPs results both in a short exposure of non-calcified tissues to the drug but also in a prolonged accumulation in bone where NBPs can also reach higher and tumoricidal concentrations. These considerations explain the relative efficacy of NBPs on tumours placed in bone tissues. A method of increasing the availability of these drugs in extra-bone tissues and increasing their plasma half-lives involves encapsulation in liposome vehicles (Harrington et al. 2002). Liposome-encapsulated clodronate, PAM and alendronate have already been produced and used for their ability to accumulate in the reticulo-endothelial system and for their macrophage-depleting properties (van Rooijen & van Kesteren-Hendrikx 2002, Danenberg et al. 2003). However, these agents have non-specific uptake in white blood cells and are, therefore, not suitable for anti-cancer therapy. Stealth liposomes (pegylated liposomes or second-generation liposomes) are more germane for anti-tumour clinical practice because they evade interception by the immune system. They are characterized by very long circulation halflives, favourable pharmacokinetic behaviour and speci fic accumulation in tumour tissues (Cattel et al. 2004). One of the first anti-cancer drugs encapsulated in pegylated liposomes and used in clinical trials was doxorubicin (Gabizon et al. 2003). More recently, the ability of doxorubicin encapsulated in stealth liposomes to be active in the treatment of brain tumour metastases has also been reported (Caraglia et al. 2005). These favourable pharmacokinetic properties of pegylated liposomes could encourage their use as NBP vehicles in order to increase the uptake of the latter in tumour sites.
Rationale-based combinations between NBPs and other biological agents
On the basis of the emerging mechanisms of action of NBPs, several combinations of NBPs and other biological agents have been designed and their activity on tumour cell proliferation has been evaluated.
ZOL and other NBPs have been combined with different biological agents based on their ability to inhibit crucial processes of protein isoprenylation. In fact, the prenyltransferases are not strictly specific and a small G protein can be the substrate for different enzymes. In fact, K-RasB, which has a classical FTase CA1A2X box (CVIM), is a substrate for FTase, but following inhibition of cellular FTase, K-RasB becomes a substrate for geranylgeranylation by GGTase-I (Gibbs 2001). Similarly, RhoB, which contains a GGTase-I CA1A2X box (CKVL), is found in both farnesylated and geranylgeranylated forms in cells (Yokayama & Gelb 2001). These events allow the alternative isoprenylation of the substrate of prenyltransferase inhibitors when FTIs are added to tumour cells. Based on the relevance of any farnesylation inhibitory effects on anti-tumour activity of the BPs, the FTI R115777 was used together with PAM or ZOL and the effects of the combination treatment on growth inhibition and apoptosis evaluated. BPs and FTI given in combination were strongly synergistic since a CI50 (the combination index of the two drugs calculated for 50% cell survival by isobologram analysis using dedicated software) of less than 0.5 was recorded (Caraglia et al. 2004). In fact, CI50 values less than 1.0 suggest synergism and values less than 0.5 suggest strong synergism in inducing growth inhibition by drug combinations (Chou & Talalay 1984). Notably, low concentrations of FTI induced a strong increase of ras expression with only a moderate reduction of ras activity that was, on the other hand, significantly reduced by the combined treatment (Caraglia et al. 2004). These data suggest that escape mechanisms for the inhibition of isoprenylation of ras might be based on the geranylgeranylation or other prenylating processes (Lee et al. 2001). The addition of FOH to cells treated with the combination abolished the effects of the BPs/FTI combination on apoptosis and on the activity of the signalling molecules. These data suggest that the synergistic growth-inhibitory and pro-apoptotic effects produced by the NBP/FTI combination involve the inhibition of both Erk and Akt survival pathways acting in these cells in a ras-dependent fashion (Caraglia et al. 2004).
Andela et al. (2002) have recently reported that the NBP alendronate and R11577 used alone had no significant effects on the growth inhibition and apoptosis of murine lung alveolar carcinoma, but showed a reduction in in vitro invasiveness when the two drugs were combined. Moreover, alendronate potentiated the in vivo anti-metastatic effects of R115777.
Imatinib mesylate, a selective inhibitor of Abl tyrosine kinase, has significant and rapid activity against chronic myelogenous leukaemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukaemia (ALL). Targeting one of the Bcr-Abl downstream signaling proteins essential for Bcr-Abl-mediated leukaemogenesis, in addition to Bcr-Abl, was intriguing. Several lines of evidence have implicated the Ras/mitogen-activated protein kinase (MAPK) signalling pathway as an important molecular target (Turhan et al. 1998, le Coutre et al. 2000, Mahon et al. 2000, Weisberg & Griffin 2000, Druker et al. 2001a,b, Hofmann et al. 2002, Hoover et al. 2002, Ottman & Hoelzer 2002, Yu et al. 2002). On the basis of these considerations Kuroda et al. (2004) have used imatinib in combination with ZOL in imatinibresponsive or -resistant AML cell lines. Interestingly, imatinib-resistant cell lines also displayed sensitivity to the growth inhibitory activity of both ZOL and PAM, and also ZOL induced a decrease of Rap-1A and ras prenylation, G2M-phase accumulation and apoptosis.
It was also reported that ZOL was able to induce growth inhibition of a small cell lung cancer (SCLC) cell line subcutaneously transplanted in nude mice and was synergetic on in vitro growth inhibition with several anti-cancer agents and had additive effects if combined with imatinib (Matsumoto et al. 2005). Another study examined the effects of combining a cyclooxygenase-2 inhibitor SC236 with ZOL and/or docetaxel in a HER-2/neu-transfected and a control human breast cancer cell line. Enhanced growth inhibition was observed in both cell lines with both the combination of docetaxel and SC236, and of docetaxel and ZOL (Witters et al. 2003).
Zhang et al. (2004) have demonstrated a differential sensitivity of breast cancer cell lines to PAM based upon differential modulation of ras protein expression induced by the NBPs. They have found that MDA-175 was a PAM-resistant cell line in which the modulation of ras expression by PAM was lost. On the basis of these findings they have used in combination with PAM, imatinib or bortezomib, a proteasome inhibitor or rapamycin, an inhibitor of the mammalian target of rapamycin (m-TOR); all combinations showed additive effects in causing inhibition of proliferation in MDA-175 cells (Zhang et al. 2004). It was also reported that another newly synthesized NBP, minodronic acid, synergized with all-trans retinoic acid, thalidomide, or interferon beta on the growth inhibition and apoptosis of myeloma cells (Yata et al. 2002). More recently, it was shown that minodronic acid has anti-proliferative activity and reduces the prenylation of Rap-1A in human RCC cells (Yuasa et al. 2005).
The findings of synergy of interaction between NBPs and other agents could reduce the NBP concentrations required for anti-tumour activity and could allow the achievement of effective in vivo levels.
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TopAbstractIntroductionBiochemical pathways as...The isoprenylation processSuggested intracellular...Clinical evidence of anti...ConclusionsReferences |
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The body of evidence accumulated on NBP mechanisms of action does suggest some innovative strategies based on the use of rationale-based drug combinations. The existence of a pro-apoptotic effect of NBPs based on the disruption of ras (or ras-like)-mediated pathways supports the combination between NBPs and other isoprenylation inhibitors such as FTIs. However, further pre-clinical investigations, eventually supported by advanced technological platforms, are required for the discovery of molecular targets of NBPs and for the optimization of their mode of administration.
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Funding |
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This work was partially supported by grants from both the Italian Ministry of Health (FSN2003 and FSN2004) and the Italian Association for Cancer Research (AIRC). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.
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