Zoledronate and variants: A New Weapon Against Tumor Cells
(Simultaneous Hif/VEGF, IGF, CSC, PI3k/Akt, chemo replacer for adjuvant?, monotherapy non-skeletal cases, weekly for BC and antiangiogenic effect, against persistent isolated cells, timing to potentiate chemo, timing w/endocrine,w/doxycycline,w/cisplatinum,w/fluvastatin, w/gossypol, w/rads, prevention, side effects, dosing, BM-EPC marker controversy, side effects thread, oral ibandronate, increased neoadj PCR, reverses GM-CSF induced growth)
Curr Cancer Drug Targets. 2010 Jan 1. [Epub ahead of print] Can we Consider Zoledronic Acid a New Antitumor Agent? Recent Evidence in Clinical Setting.
Santini D, Virzi V, Fratto ME, Bertoldo F, Sabbatini R, Berardi R, Calipari N, Ottaviani D, Ibrahim T.
Medical Oncology, University Campus Bio-Medico, Rome, Italy d.santini@unicampus.it.
New emerging data suggest that bisphosphonates may exert antitumor properties. Preclinical studies have demonstrated that zoledronic acid (ZA) can induce direct and indirect antitumor activities such as inhibition of angiogenesis, invasion and adhesion of tumor cells, and overall tumor progression, stimulation of adoptive and innate immunity and emerging evidence suggests that the use of these agents may prevent the development of skeletal and extra skeletal metastases. This review will critically describe the new growing evidence of antitumor activity exerted by bisphosphonates in cancer patients, both in metastatic disease and in the adjuvant setting. The effects of bisphosphonates on survival in metastatic cancer patients will be described and evidence from retrospective analyses and prospective studies will be critically reported. The early evidence from prospective analyses of survival impact by ZA in the adjuvant setting in breast cancer will be discussed together with the recently published results of the ABCSG-12 study. A new "era" for bisphosphonates in the oncological setting is opening. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of adjuvant and metastatic cancer therapies.
PMID: 20088792 [PubMed - as supplied by publisher]
Zoledronic acid - a multiplicity of anti-cancer action.
Yuasa T, Kimura S, Ashihara E, Habuchi T, Maekawa T.
Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan. yuasa@doc.med.akita-u.ac.jp
Bisphosphonates (BPs) are inhibitors of bone-resorption and have become the current standard of care for preventing skeletal complications associated with bone metastases. Among BPs, zoledronic acid (ZOL) has the strongest activity of anti-bone resorption and shows diverse direct anti-cancer effects in vitro. Some chemical and biological characteristics of ZOL indicate the potential for in vivo growth inhibition and the mechanisms responsible for the observed anti-cancer effects are beginning to be elucidated. ZOL inhibits farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. Consequently, it inhibits the prenylation of small G-proteins such as Ras, Rap1, Rho and Rab, reduces the signals they mediate, and thereby prevents the growth, adhesion/spreading, and invasion of cancer cells. ZOL, which has a high affinity for mineralized bone, rapidly localizes to bone, resulting in therapeutically effective local concentrations for the cancer cells in bone. ZOL also blocks osteolysis and osteoclastgenesis, thus preventing the release of various growth factors which are abundantly stored in bone. Moreover, ZOL stimulates gammadelta T cells, which play important roles in innate immunity against cancer. In addition, ZOL is also a potent inhibitor of angiogenesis, probably due to the modification of various angiogenic properties of endothelial cells. Furthermore, ZOL synergizes with a variety of anticancer agents including chemotherapeutic drugs, molecular targeted agents, and other biological agents. Based on these potential anti-cancer properties, several clinical trials have been initiated to test the combination of ZOL and other agents. The accumulated encouraging evidence to date indicate that ZOL is an attractive anti-cancer agent which promises to be the next exciting therapy for patients with various cancers.
Jpn J Clin Oncol. 2009 Nov;39(11):745-50. Epub 2009 Oct 6. A case of bone, lung, pleural and liver metastases from renal cell carcinoma which responded remarkably well to zoledronic acid monotherapy.
Miwa S, Mizokami A, Konaka H, Izumi K, Nohara T, Namiki M.
Department of Integrative Cancer Therapy and Urology, 13-1 Takara-machi, Kanazawa City 920-8640, Japan.
Herein, we report a rare case in which bisphosphonate zoledronic acid (ZA) effectively treated not only multiple bone metastases but also lung, pleural and liver metastases from renal cell carcinoma (RCC). Recently, ZA is used to treat skeletal-related events (SREs) such as bone pain caused by bone metastasis from many kinds of cancer. The patient in the present report had multiple bone metastases from RCC. Remarkable improvement of the bone metastasis was observed following treatment with ZA at a dosage of 4 mg administered once every 4 weeks. Moreover, lung, pleural and liver metastases also diminished markedly in size in response to the treatment. The metastases have shown no progression for 20 months since starting the ZA treatment. We believe that the present report is the first of its kind announcing that ZA monotherapy has been effective for lung, pleural and liver metastases from RCC.
PMID: 19808839 [PubMed - indexed for MEDLINE]
Curr Cancer Drug Targets. 2009 Nov;9(7):791-800. Cutting the limits of aminobisphosphonates: new strategies for the potentiation of their anti-tumour effects.
Marra M, Abbruzzese A, Addeo R, Del Prete S, Tassone P, Tonini G, Tagliaferri P, Santini D, Caraglia M.
Department of Biochemistry and Biophysics, II University of Naples, Via Costantinopoli no16, 80138 Naples, Itlay.
Therapy with aminobisphosphonate (N-BPs), and zoledronic acid (ZOL) especially, has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that N-BPs exert their direct or indirect anti-tumour effects on cancer growth factor release, cancer cell adhesion, invasion and viability, cancer angiogenesis and cancer cell apoptosis. Here, we will discuss the molecular mechanisms of the antitumour effects induced by ZOL. Despite their well-established in vitro anti-tumour effects N-BPs have not clear in vivo anti-tumour activity in humans. The bases of these discrepancies will be discussed in the text with a special focus on the pharmacokinetic limits of N-BPs. Moreover, the following molecular and pharmacological strategies in order to overcome N-BPs limitations will be described: i) development of pharmacological combinations with other biological agents; ii) finding of new molecular targets of N-BPs; iii) development of new pharmacological formulations of N-BPs. Finally, a new scenario of integrated bio-medicine and pharmacology will be depicted in order to drive the optimization of anti-cancer activity of N-BPs.
PMID: 20025567 [PubMed - in process]
Bone. 2009 Dec;45(6):1153-60. Epub 2009 Aug 21. The level of ATP analog and isopentenyl pyrophosphate correlates with zoledronic acid-induced apoptosis in cancer cells in vitro.
Mitrofan LM, Pelkonen J, Mönkkönen J.
Faculty of Pharmacy, Department of Pharmaceutics, University of Kuopio, Finland.
Bisphosphonates are potent inhibitors of osteoclast function widely used to treat excessive bone resorption associated, e.g., with bone metastases. They have also antitumor activity. However, it is unclear whether this reflects an indirect effect via inhibition of bone resorption or a direct antitumor effect. Nitrogen-containing bisphosphonates (N-BPs), including zoledronic acid (ZOL), act by inhibiting farnesyl pyrophosphate synthase (FPPS). The mevalonate pathway is blocked and the accumulation of isopentenyl pyrophosphate (IPP) consequently occurs. IPP is conjugated to AMP to form a novel ATP analog (ApppI). The present study was undertaken to clarify whether IPP and/or ApppI has a direct involvement in apoptosis caused by ZOL in different cancer cell lines. There are marked differences in ZOL-induced ApppI formation between different cancer cell lines. On this basis, we selected three cancer cell lines that differ significantly from each other in their ZOL-induced IPP and ApppI accumulation: human estrogen-dependent (MCF7) and estrogen-independent (MDA-MB 436) breast cancer cell lines and a human myeloma cell line (RPMI 8226). The amount of IPP/ApppI correlated with the capacity of cells to undergo apoptosis. Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, blocks both IPP and ApppI formation and to some degree ZOL-induced apoptosis in a cell line-dependent manner. In addition, lovastatin (LOV), an inhibitor of the enzyme HMGCoA reductase, completely blocks IPP/ApppI formation as determined by mass spectrometry analysis, but enhances apoptosis. In conclusion, the current data suggest that ZOL-induced IPP/ApppI formation can contribute to ZOL-induced apoptosis. This mechanism and the inhibition of protein prenylation, both outcomes of FPPS inhibition in mevalonate pathway, seem to act in concert in ZOL-induced apoptosis in cancer cells.
There is growing scientific evidence that better targeting ofthe bisphosphonates to cells outside bone could more likelybe achieved by more frequent administration of low doses (2,3). These data are supported by the pharmacokinetic profileof zoledronic acid (ZA). This bisphosphonate is prevalentlyaccumulated into the bone and constantly dismissed in the circulationat very low concentrations by the bone turnover. As a consequence,its circulating plasma levels are low and short lasting. Forthis reason, repeated pulses of ZA could be useful in the maintenanceof active plasma concentrations of ZA. Thus, metronomic (commonlyidentified as intermittent administration of low doses of anticancerdrugs) bisphosphonate administration may lead to significantintracellular accumulation over time in tumor cells.Although the precise mechanism of this effect is still not wellknown, it is reasonable to hypothesize that clinical fractionateddosing of ZA may inhibit several antiangiogenic-related cascadesat different cellular and molecular levels. It has been shownthat ZA may affect angiogenesis (i.e., the formation of newvessels by sprouting of preexisting mature endothelial cellsand inhibiting endothelial cell adhesion and migration) butonly at higher concentrations (4). On the other hand, we mayhypothesize that, at lower concentrations, such as during metronomicadministration, ZA could affect vasculogenesis (i.e., the creationof primordial vessels from endothelial progenitor cells derivedfrom bone marrow; ref. 5). The endothelial progenitor cellspossess the ability to migrate, colonize, proliferate, and,ultimately, differentiate into endothelial lineage cells appearingto contribute to tumor vessel formation by incorporating intothe neoendothelium. (6). The inhibition of endothelial progenitorcell mobilization results in retardation of tumor growth (6).Vascular endothelial growth factor (VEGF) induces the proliferation,differentiation, and chemotaxis of endothelial progenitor cellsand is essential for survival of these progenitors (7). It hasbeen shown that circulating endothelial cell levels can be alteredby chemotherapeutic and antiangiogenic treatments, such as metronomicchemotherapy or VEGF inhibitors (8). For all these reasons,we could hypothesize that fractioned and intermittent administrationof ZA may target directly EPCs. Therefore, based on this stimulatinghypothesis, we intend to investigate the effects in humans ofZA therapy on the number and functions of circulating EPCs.
Effect of metronomic use of zoledronic acid (ZOL) on antitumor and antiosteoclastic effects in breast cancer patients with bone metastasis.
Author(s): H. Xi-Chun, X. Zhao, X. Xu, H. Guo, Z. Wang, X. Guo, J. Chen, J. Wu, Z. Shao, J. Li, B. Zhu; Cancer Hospital of Fudan University, Shanghai, China
Abstract: Background:Zoledronic acid (ZOL) can reduce the risk of skeletal-related events (SREs) and may have direct and indirect antitumor effects, which have been shown in animal models, pilot clinical studies as well as in recent phase III randomized trials. However, the pharmacokinetics of the drug in breast cancer patients remains to be elucidated and optimized. The purpose of this randomized study was to compare the effects of ZOL on osteoclasts and angiogenesis between a weekly low-dose versus a conventional dosage. Methods:Sixty breast cancer patients with bone metastases were recruited in this randomized phase II clinical study. The participants either received ZOL 1mg IV weekly for 4 doses or a single dose of ZOL 4mg IV. No other antitumor treatments were administered. During the first month after initial infusion of ZOL, serial blood samples were collected on day 1, 15 and 29 measuring markers for bone resorption (NTx), angiogenesis (VEGF), and tumor burden (CEA and CA15-3). Results:Compared to a single-dose administration, weekly low dose of ZOL resulted in a greater reduction in serum levels of VEGF and NTx, with a significant trend over time during one month observation. There were no statistically significant differences in circulating levels of CEA and CA15-3 between the two dosing regimens. Patients who received metronomic ZOL had a longer median time to disease progression (TTP) (7.0 months, 95%CI, 6.1-7.9 months) than those who had a single dose of ZOL (2.8 months, 95%CI, 0-5.7 months; p=0.076). Conclusions: The metronomic use of low-dose ZOL 1 mg appeared to be more effective than the conventional regimen in the long-lasting reduction of VEGF and NTx, and in prolonging TTP. This dosing schedule should be further assessed in phase III trials as we demonstrated that ZOL 1mg has greater antitumor properties in our study. Cancer Therapy: Clinical
Repeated Intermittent Low-Dose Therapy with Zoledronic Acid Induces an Early, Sustained, and Long-Lasting Decrease of Peripheral Vascular Endothelial Growth Factor Levels in Cancer Patients
Daniele Santini1, Bruno Vincenzi1, Sara Galluzzo1, Fabrizio Battistoni2, Laura Rocci1, Olga Venditti1, Gaia Schiavon1, Silvia Angeletti2, Federica Uzzalli1, Michele Caraglia3, Giordano Dicuonzo2 and Giuseppe Tonini1Authors' Affiliations:1 Medical Oncology and 2 Department of Laboratory Medicine, University Campus Bio-Medico, Rome, Italy, and 3 Experimental Pharmacology Unit, National Cancer Institute of Naples "Fondazione G. Pascale," Naples, Italy Requests for reprints: Daniele Santini, Medical Oncology, University Campus Bio-Medico, 00155 Rome, Italy. Phone: 39-6-2254-1737; Fax: 39-6-2254-1520; E-mail: d.santini@uicampus.it. Purpose: On the basis of stimulating data on animals reportingthat weekly regimens of zoledronic acid (ZA) were effectivein reducing skeletal tumor burden, we designed a study on humansto investigate the potential antiangiogenic role of a weeklylow-dose therapy with ZA in patients with malignancies. Experimental Design: Twenty-six consecutive patients with advancedsolid cancer and bone metastases received 1 mg of ZA every weekfor four times (days 1, 7, 14, and 21) followed by 4 mg of ZAwith a standard 28-day schedule repeated thrice (days 28, 56,and 84). Patients were prospectively evaluated for circulatinglevels of vascular endothelial growth factor (VEGF) just beforethe beginning of drug infusion (0) and again at 7, 14, 21, 28,56, and 84 days after the first ZA infusion. Results: The median VEGF basal value showed an early statisticallysignificant (P = 0.038) decrease 7 days after the first 1-mginfusion of ZA. This effect on VEGF-circulating levels persistedalso after the following 1-mg infusions at 14 (P = 0.002), 21(P = 0.001), and 28 days (P = 0.008). Interestingly, the decreaseof VEGF-circulating levels persisted also at each programmedtime point during the second phase of the study (ZA 4 mg every4 weeks). No significant differences were recorded in plateletlevels, WBC count, or hemoglobin concentration before and aftereach ZA infusion. Conclusions: In the present study, we report that a repeatedlow-dose therapy with ZA is able to induce an early significantand long-lasting decrease of VEGF levels in cancer patients.
Cancer Biol Ther. 2010 Sep 8;10(6). [Epub ahead of print] Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: Phase I ZANTE trial.
Background: Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid ANd TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC. Results: The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B. Patients and Methods: Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50 mg/m(2)) in combination with a fixed dose of ZOL (2 mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL. Conclusions: The bi-weekly combination of DTX (50 mg/m(2)) followed by ZOL was feasible and show promising anti-tumor activity.
PMID: 20657175 [PubMed - as supplied by publisher]
Metronomic weekly use of zoledronic acid for breast cancer with
bone metastases
Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation.
Yamada J, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, Asakage M, Okaji Y, Shuno Y, Nishikawa T, Tanaka J, Takahashi K, Nagawa H.
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan. jymda-tky@umin.ac.jp
BACKGROUND: Zoledronic acid (ZOL) is clinically available for the treatment of skeletal complications. In preclinical studies, strong anti-cancer activities against breast cancer, prostate cancer, and leukemia were reported. It also inhibited the proliferation of cultured human endothelial cells, suggestive of an anti-angiogenic activity. Since ZOL has the tendency to accumulate in bone, we investigated the effect of ZOL on endothelial progenitor cells (EPCs), which originate from the bone marrow, and play important roles in angiogenesis. MATERIALS AND METHODS: Human peripheral blood mononuclear cells were cultured for 7 d to differentiate into EPCs. Cells were treated without/with ZOL or with geranylgeraniol (GGOH). Their endothelial phenotype was confirmed by the expression of CD144 and vascular endothelial growth factor receptor 2 and the tube-like formation ability on Matrigel (Becton Dickinson, Bedford, MA). Annexin V/propidium iodide staining was used to analyze apoptosis. RESULTS: ZOL treatment, even at low doses, from d 2 to 7 of culture resulted in impaired EPC differentiation and could be restored by co-treatment with GGOH. On the other hand, treatment of putative EPCs with ZOL at concentrations higher than 10 mum resulted in induction of apoptosis.
CONCLUSION: ZOL dose-dependently inhibited the differentiation of EPCs, the effect being observed even at low drug levels. At high concentrations, ZOL also induced the apoptotic death of putative EPCs. Since GGOH restored the inhibitory effect of ZOL on EPCs differentiation, the effect of ZOL appears to be dependent on the inhibition of prenylation of small-G-proteins. From these findings, we conclude that ZOL could be a potential anticancer agent by inhibiting angiogenesis.
Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes.
Todaro M, D'Asaro M, Caccamo N, Iovino F, Francipane MG, Meraviglia S, Orlando V, La Mendola C, Gulotta G, Salerno A, Dieli F, Stassi G.
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Colon cancer comprises a small population of cancer stem cells (CSC) that is responsible for tumor maintenance and resistant to cancer therapies, possibly allowing for tumor recapitulation once treatment stops. We previously demonstrated that such chemoresistance is mediated by autocrine production of IL-4 through the up-regulation of antiapoptotic proteins. Several innate and adaptive immune effector cells allow for the recognition and destruction of cancer precursors before they constitute the tumor mass. However, cellular immune-based therapies have not been experimented yet in the population of CSCs. Here, we show that the bisphosphonate zoledronate sensitizes colon CSCs to Vgamma9Vdelta2 T cell cytotoxicity. Proliferation and production of cytokines (TNF-alpha and IFN-gamma) and cytotoxic and apoptotic molecules (TRAIL and granzymes) were also induced after exposure of Vgamma9Vdelta2 T cells to sensitized targets. Vgamma9Vdelta2 T cell cytotoxicity was mediated by the granule exocytosis pathway and was highly dependent on isoprenoid production by of tumor cells. Moreover, CSCs recognition and killing was mainly TCR mediated, whereas NKG2D played a role only when tumor targets expressed several NKG2D ligands. We conclude that intentional activation of Vgamma9Vdelta2 T cells by zoledronate may substantially increase antitumor activities and represent a novel strategy for colon cancer immunotherapy.
Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1α/VEGF signaling pathways in human breast cancer cells
International Journal of Cancer, 08/12/09
Tang X et al. - In a trial to investigate potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells, it was demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in inhibition of tumor angiogenesis in breast cancer cells.
Methods
It was tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis.
Results
Both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1α protein accumulation and VEGF expression in MCF-7 cells.
Mechanistically, either pamidronate or clodronate did not affect mRNA expression of HIF-1α, but they apparently promoted the degradation of IGF-1-induced HIF-1α protein.
The presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1α protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting inhibition of protein synthesis.
The inhibitory effects of bisphosphonates on the HIF-1α/VEGF axis are associated with inhibition of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways.
The breast cancer revolution that saves women from chemo
By Jerome Burne
Last updated at 11:10 PM on 16th November 2009
A diagnosis of breast cancer usually means having chemotherapy to stop the cancer coming back. But if you're a patient in Austria, you're unlikely to be given chemo as a treatment.
And yet you'll do better than patients who undergo the treatment, as well as avoiding the gruelling side effects, says a leading Austrian cancer specialist in an article to be published in the medical magazine, The Lancet, later this month. 'There has been too much emphasis on adding chemotherapy to breast cancer treatment,' the article's author, Professor Michael Gnant, told the Mail. 'It's toxic, with often too little gain. In Austria, we've been treating breast cancer without chemotherapy for years - with great success.'
Beyond chemo: Doctors in Austria look very closely at the type of tumour a breast cancer patient has and treat it according to how it's likely to respond
In the UK, the standard treatment for breast cancer is surgery to remove the tumour - and then drugs to reduce the risk of the cancer recurring.
If you're one of the 60 per cent of patients whose cancer is stimulated by the hormone oestrogen, you'll get a drug to block it - most likely Tamoxifen - and then chemotherapy as well. Those patients whose tumours don't respond to hormones just get chemotherapy.
Chemotherapy works by targeting fast-growing cells, such as those in a tumour. Unfortunately, there are many other fastgrowing cells in the body - in the hair, skin, lining the digestive system and the bone marrow (where blood cells are made).
That's why chemotherapy can cause side effects such as nausea, diarrhoea, hair loss, sores in the mouth and throat, and a drop in the number of blood cells that fight infections. In Austria, cancer specialists look more closely at the type of tumour each patient has - and treat it according to how it's likely to respond. According to Professor Gnant's research, patients there do just as well - if not better - than those who have chemotherapy.
'If a woman had a tumour removed that was very responsive to oestrogen, then I'll probably treat her only with a drug that blocks oestrogen ,' says Professor Gnant, who is based at Vienna Medical University.
In the UK, even if your tumour is very hormone responsive, you are still likely to be given three different types of chemotherapy drugs as well.
The Austrian approach - looking closely at the biology of individual tumours - should become the standard, a major international conference recommended earlier this year.
British experts are aware of this approach, but are more cautious about adopting it.
'It is certainly the way forward,' says Dr Peter Canney, consultant clinical oncologist at the Beatson Cancer Care Centre in Glasgow. 'However, we're not yet good enough at spotting all those who can do without chemotherapy.'
this is not the only innovation in breast cancer care in Austria. To stop cancer returning-some patients are being given bisphosphonates - drugs usually used to treat osteoporosis.
Medicine mix: Some breast cancer patients are given drugs typically used to treat osteoporosis. Pictured is an X-ray of a femur fractured due to the bone-thinning disease
In a recent major trial, published in the New England Journal of Medicine, patients who had just one injection of a high-dose bisphosphonate every six months had a 33 per cent greater chance of remaining cancer-free. So how do bone drugs help with cancer? 'When cells from a breast tumour spread, they often go to the bone,' explains Dr Trevor Powles, a British expert and one of the first oncologists to test the benefits of bisphosphonates on breast cancer. Once they reach the bone, the cancer cells stimulate bone-destroying cells. This, in turn, produces growth factors, which boost the cancer.
'It's a vicious circle,' says Dr Powles. 'Giving a bisphosphonate that kills off the bone-destroying cells actually makes a lot of sense.'
Professor Gnant believes that the evidence for bisphosphonates is good enough for some patients to use it right away.
'If my wife, who hasn't been through the menopause, had cancer, I'd make sure she got it,' he says. 'However, I wouldn't do the same for my mother because the data for post-menopausal women isn't clear yet.'
And the benefits of bisphosphonates may not be limited to breast cancer; they may also improve the treatment of cancers such as lung and prostate. Indeed, it was reported last week that bisphosphonates and breast cancer drugs could destroy cervical cancer.
Professor Gnant believes that as well as migrating into the bone, some cancer cells travel to the bone marrow, where they lurk. This is why the bone drugs could have a much wider benefit. 'Bisphosphonates can affect bone marrow in general, making it less of a sanctuary for the tumour cells so they are less likely to spread,' he says.
So should British patients be seeking this new treatment?
Some experts here, such as Dr Powles at Parkside Oncology Clinic in London, have already been looking at the potential for bisphosphonates. A few years ago, he conducted a trial giving very high daily doses of oral osteoporosis drugs to more than a 1,000 breast cancer patients and found they improved drug-free survival.
The results from two other trials didn't show the same benefit, so the treatment was not licensed. Now, Gnant's results with a stronger drug (Zometa) may change our approach.
'The results are encouraging, but I'd still want to see some more data,' says Dr Powles.
He and other UK experts are waiting until next year before deciding whether to push for bisphosphonates to be widely used. This is when a bigger UK trial involving about 3,000 patients on higher and more frequent doses of Zometa is due to report.
But could bone drugs replace chemotherapy? Professor Gnant hopes they will at the very least reduce its use. 'Chemotherapy can be a valuable addition to breast cancer treatment, but evidence suggests it can be used more sparingly,' he says.
A new drug could prove to be more effective in cancer treatment as tests show that it is about 200 times more active in killing tumor cells. The active agent comes from a class of drugs called bisphosphonates and it was developed by a team of 24 researches from four countries.
Although they were primarily conceived as a treatment for osteoporosis and other bone diseases, recent discoveries show that bisphosphonates also have inhibitory effects on enzymes such as FPPS and GGPPS, which leads to killing cancer cells with more efficiency that the drugs aimed at the protein Ras (which presents mutations in a third of human cancer cells and represented a less successful target for drug developers).
Derived from bisphosphonates (and used alongside hormonal treatment) the drug zoledronate proved effective in reducing the recurrence of breast cancer in premenopausal women with estrogen-receptor-positive breast cancer and hormone-refractory prostate cancer in men but its efficiency proved diminished by the fact that it binds faster to the bone rather than getting to the tissues where it was needed.
In trying to find a new drug that wouldn’t have this side effect and which would also inhibit more than just one enzyme in the cancer cell’s survival pathway, a new study was carried, led by Professor Eric Oldfield of the University of Illinois. The research team managed to produce drugs that bonded to multiple enzyme targets but not to bone, of which BPH-715 effectively inhibited tumor cell growth and invasiveness and killed tumor cells in mice. BPH-715, as well as zoledronate, also has the effect of increasing the production of gamma delta T-cells, immune system cells that also kill tumor cells.
Br J Cancer. 2010 Mar 16. [Epub ahead of print] The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer.
Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, Gil M, Ritchie D, Passos-Coelho JL, Wheatley D, Burkinshaw R, Marshall SJ, Thorpe H.
Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Sheffield, UK.
Background:Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups.Methods:In total, 205 patients received neoadjuvant CT+/-ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers.Results:Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5-20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315).Conclusion:These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.British Journal of Cancer advance online publication, 16 March 2010; doi:10.1038/sj.bjc.6605604 www.bjcancer.com.
PMID: 20234364 [PubMed - as supplied by publisher]
Anticancer Res. 2010 May;30(5):1807-13. Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer.
BACKGROUND: There is strong evidence for the isolated tumour cells (ITCs) in the bone marrow of breast cancer patients having prognostic impact both at primary diagnosis and during recurrence-free follow-up. The goal of this study was to investigate the therapeutic efficacy of zoledronate on the persistence of ITC. PATIENTS AND METHODS: A total of 172 primary breast cancer patients without evidence of distant recurrence but detection of ITC in bone marrow were followed up. Zoledronate was administered every 4 weeks for 6 months to 31 patients who had completed surgery and adjuvant chemotherapy. In a matched-pair analysis, these patients were compared to 141 patients who did not receive additional zoledronate treatment. The bone marrow was re-examined after a median of 7.9 months (SD 0.89) and 11.5 months (SD 12.41; p=0.11), respectively. Patients were followed-up prospectively for a median of 39 months after the first aspiration. RESULTS: While ITCs were detected in all 172 patients at the time of first bone marrow aspiration, ITCs were detected in four patients (13%) following 6 months of zoledronate therapy in contrast to 38 patients (27%) of the control group (p=0.099). The reduction in cell numbers between the first and second aspiration reached statistical significance in the zoledronate group (p=0.02 vs. p=0.14). Persistent ITCs at the follow-up aspiration were associated with reduced recurrence-free survival (p=0.05). CONCLUSION: These results indicate a potential antineoplastic effect of the cell cycle-independent agent zoledronate on persisting ITCs in a dormant state.
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