Br J Cancer. 2010 Feb 16. [Epub ahead of print]
Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction.
TEXT
Neville-Webbe HL,
Coleman RE,
Holen I.
Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield S10 2SJ, UK.
Background:Aromatase inhibitors are widely used in the treatment of oestrogen receptor-positive post-menopausal breast cancer. These patients may also be receiving the bisphosphonate, zoledronic acid (ZA) to prevent bone loss or reduce skeletal morbidity in the setting of advanced disease. The potential biological interaction of these two drugs in breast cancer has not been assessed.Methods:Aromatase-expressing breast cancer cells were treated with letrozole and ZA either simultaneously or in sequence, and the resulting apoptosis was assessed by staining with Hoechst 33342 and propidium iodide and examined using a fluorescent inverted Leica DMIRB microscope and a UV filter.Results:
We found that letrozole and ZA induce levels of apoptosis in breast cancer cells in vitro that are significantly greater compared with treatment with each drug alone. However, this potentially, synergistic relationship is drug-sequence dependent, occurring only when cells are treated with letrozole, followed by ZA. The converse sequence, or administering drugs simultaneously, induces levels of apoptosis no greater than each drug alone.Conclusion:Owing to the enhanced anti-tumour efficacy of sequential drug administration, our findings may indicate that, for post-menopausal women who require treatment with letrozole, ZA should also be considered.British Journal of Cancer advance online publication, 16 February 2010; doi:10.1038/sj.bjc.6605579
www.bjcancer.com.
PMID: 20160726 [PubMed - as supplied by publisher]
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In combination, ZA and letrozole have potential for synergistic induction of MCF7-Ca cells in vitro. However, increased induction of apoptosis only occurred when cells were treated with letrozole followed by ZA. ‘Letrozole then ZA’ induced a level of apoptosis that was over eight times greater than that caused by letrozole alone, and 4.8 times greater than treatment with ZA alone. The ZA has consistently shown potential for synergistic interaction with drugs commonly used in breast cancer. This includes a
combination with paclitaxel (Jagdev et al, 2001; Neville-Webbe et al, 2006), tamoxifen (Jagdev et al, 2000) and doxorubicin (Neville-Webbe et al, 2005). In our earlier study with ZA and chemotherapy drugs, we have similarly found that sequential administration of drugs is of paramount importance for inducing maximal (potentially synergistic) levels of apoptosis. For breast cancer cells treated with ZA in combination with either doxorubicin or paclitaxel, as with letrozole, cells had to be treated with the chemotherapy drug first, and thereafter with ZA. Treating cancer cells with the reverse sequence, or even simultaneously, was either antagonistic or, at best, additive, and the same patterns were seen here with letrozole. Our group recently evaluated this
sequence-dependent synergy in an in vivo soft-tissue breast tumour model (Ottewell et al, 2008a, b). Using clinically relevant doses of doxorubicin and ZA, inhibition of tumour growth was shown to be sequence dependent with doxorubicin followed by ZA,
leading to inhibition of tumour growth associated with evidence of enhanced tumour cell apoptosis and reduced proliferation. The biological effects of letrozole and ZA are largely mediated through the induction of apoptosis. It is likely that this is enhanced through inhibition of the mevalonate pathway. Using an intermediary of this pathway (GGOH), apoptosis was reduced by 50% for cells treated with the sequence ‘ letrozole then ZA’. Inhibition of the mevalonate pathway by nitrogen-bisphosphonates is integral for inducing a variety of effects including apoptosis of osteoclasts (Amin et al, 1992), breast cancer cells (Jagdev et al, 2001), prostate cancer cells (Oades et al, 2003), myeloma cells (Shipman et al, 1998) and inhibition of tumour cell invasion (Denoyelle et al, 2003). Furthermore, inhibition of this pathway also contributes to the apoptosis induced when breast (and prostate) cancer cells are treated in combination with ZA and doxorubicin (Neville-Webbe et al, 2005), or when breast cancer cells are treated with ZA and paclitaxel (Neville-Webbe et al, 2006).
Although in vitro and in vivo studies have limited implications for the clinical setting, it is interesting to note a recent update of the ZO-FAST study (Eidtmann et al, 2008). This clinical trial assesses the effects of ZA on letrozole-induced bone loss in postmenopausal
women with early breast cancer. Patients are randomised to either combined letrozole and ZA (4 mg every 6 months) or letrozole alone. A recent update, with a 36-month
follow-up, suggested a better outcome for those treated with the combination, with a 41% risk reduction in cancer recurrence. Although these results are preliminary, and the trial was not specifically set up to address the anti-tumour potential of ZA in patients
receiving letrozole, they add to the growing evidence of the direct anti-cancer effects of this bisphosphonate in combination with other drugs, including endocrine treatments. Similarly, in the ABCSG 12 trial of pre-menopausal breast cancer patients (Gnant et al, 2009), 1803 patients received ovarian suppression with goserelin and were then randomised to receive either tamoxifen or the AI anastrazole, with or without ZA (4mg infusions every 6 months for 3 years). No significant differences in disease-free survival were seen between tamoxifen and AI. However, the group receiving ZA had a statistically significant 36% reduction in the risk of disease recurrence, compared with patients receiving endocrine therapy alone (P¼0.01). The reduction in metastatic events was not confined to a reduction in the frequency of bone metastases alone,
but also applied to distant metastatic sites, loco-regional recurrence rates and cancer of contralateral breast. Reduction of metastases outside the skeleton adds to the growing evidence that the antitumour effects of ZA are not confined to the bone, and such antitumour effects may be enhanced by combination with other drugs.
In summary, letrozole has anti-tumour activity (which is largely through induction of apoptosis) when used alone under culturemedia conditions that mimic the post-menopausal state. When combined with ZA, there is potential for a synergistic induction of apoptosis, but only when cancer cells are treated with letrozole followed by ZA. This may have positive implications for postmenopausal patients receiving both these drugs in the clinical setting.
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Though not reproducible using a very low concentration of ZA, synergy is induced with 10 mM, a concentration that could be achieved within the bone microenvironment.
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Breast Cancer Res. 2006;8(4):R52.
In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells.
FULL TEXT
Ural AU,
Avcu F,
Candir M,
Guden M,
Ozcan MA.
Department of Hematology, Gulhane Military Medical Faculty, Ankara, Turkey.
aural@gata.edu.tr
INTRODUCTION: Bisphosphonates are mostly used in the treatment of bone metastases. They have been shown to act synergistically with other chemotherapeutic agents. It is not known, however, whether similar synergistic effects exist with radiation on breast cancer cells. METHODS: Human MCF-7 breast cancer cells were treated with up to 100 microM zoledronic acid, were irradiated with up to 800 cGy or were exposed to combinations of both treatments to determine the antiproliferative effects of zoledronic acid and radiation. RESULTS:
Zoledronic acid and radiation caused a dose-dependent and time-dependent decrease in cell viability (approximate 50% growth inhibition values were 48 microM and 20 microM for 24 hours and 72 hours, respectively, for zoledronic acid and 500 cGy for radiation). A synergistic cytotoxic effect of the combination of zoledronic acid and radiation was confirmed by isobologram analysis. CONCLUSION: These data constitute the first in vitro evidence for synergistic effects between zoledronic acid and radiation. This combination therapy might thus be expected to be more effective than either treatment alone in patients with metastatic breast carcinoma.
PMID: 16925824 [PubMed - indexed for MEDLINE]
pn 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.
J Exp Clin Cancer Res. 2010 Jul 30;29:102.
Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: a paradigm of synergistic molecular targeting treatment for ovarian cancer.
Karabulut B,
Karaca B,
Varol U,
Muslu U,
Cakar B,
Atmaca H,
Kisim A,
Uzunoglu S,
Uslu R.
Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey.
FREE TEXT
Abstract
BACKGROUND: Ovarian cancer is the most fatal gynecologic malignancies in the world. Although, platinum based treatments are widely used, the disease becomes treatment refractory within two years, and novel treatment options should be searched.
All- trans retinoic acid (ATRA) induces growth arrest, differentiation and cell death in some types of cancer cells and its combination with various anticancer agents results in enhanced cytotoxicity. Zoledronic acid is a common bisphosphonate known for its anticancer effects beyond its current use in the treatment of cancer-induced bone disease. We aimed to investigate the possible additive/synergistic effect of both agents in OVCAR-3 and MDAH-2774 ovarian cancer cell lines, since both agents show superiority to conventional cytotoxics in terms of adverse events.
METHODS: XTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. OligoGeArray which consists of 112 apoptosis related genes was used to elucidate the genetic changes within cancer cells. To validate our oligoarray results, quantitative real-time PCR was performed on four selected genes that were maximally effected by the combination treatment: lymphotoxin beta receptor (LTBR), myeloid cell leukemia-1 (MCL-1), tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), TNFRSF1A-associated death domain protein (TRADD).
RESULTS: We demonstrated that
a novel combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in both ovarian cancer cells. While the combination therapy significantly induced proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), TRADD and caspase 4, some of the antiapoptotic genes such as members of MCL-1, LTBR, BAG3 and Bcl-2 family members were inhibited.
CONCLUSIONS: These are the preliminary molecular results of a novel combination treatment of ATRA and zoledronic acid, with fewer side effects as compared to conventional cytotoxic agents. With additional experimental analysis,
it may serve as a good option for the treatment of refractory and elderly ovarian cancer patients, for whom there exists very limited choice of treatment.
PMID: 20673323 [PubMed - in process]PMCID: PMC2924277Free PMC Article
Mol Biol Rep. 2010 Mar 28. [Epub ahead of print]
Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and zoledronic acid in hormone-refractory prostate cancer cell lines.
Karabulut B,
Karaca B,
Atmaca H,
Kisim A,
Uzunoglu S,
Sezgin C,
Uslu R.
Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey.
TEXT
AbstractWe report that all-trans retinoic acid (ATRA) in combination with zoledronic acid has strong synergistic cytotoxic and apoptotic effects against human hormone- and drug-refractory prostate cancer cells, PC-3 and DU-145, in a time- and dose-dependent manner. We further investigated the effect of the combination treatment on the apoptotic process by both oligoarray and protein array analysis in DU-145 cells, in which the drug combination shows much more strong synergistic effects, as compared to PC-3 cells. Moreover, we have also performed real time-PCR array analysis to validate oligoarray results. We demonstrated that
the combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in human androgen-and drug refractory prostate cancer cells DU-145, at either transcriptional or translational levels. While expression of proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), Bad, Bax, Fas, FADD are induced with the exposure of the combination, expression of antiapoptotic genes or proteins such as members of inhibitor apoptosis family (IAPs), MCL-1, LTBR, p53 and bcl-2 are reduced. Because this novel combination treatment has fewer side effects than is generally the case with conventional cytotoxic agents, this regimen may be a good option for treatment of elderly prostate cancer patients.
PMID: 20349282 [PubMed - as supplied by publisher]
Int J Urol. 2009 Sep;16(9):726-31; discussion 731-2.
Docetaxel-based chemotherapy with zoledronic acid and prednisone in hormone refractory prostate cancer: factors predicting response and survival.
Nayyar R,
Sharma N,
Gupta NP.
Department of Urology, All India Institute of Medical Sciences, New Delhi, India.
OBJECTIVES: To evaluate the efficacy of docetaxel/prednisone and zoledronic acid in hormone refractory prostate cancer (HRPC) patients and to analyze prognostic factors predicting overall survival. METHODS: Forty-four HRPC patients were given docetaxel (75 mg/m(2)), prednisone and zoledronic acid (4 mg) every three weeks. Overall and progression-free survival curves were calculated. Using the log-rank test, variables predicting overall survival (age, Gleason score, baseline prostate-specific antigen [PSA], percentage PSA decline, nadir PSA, number of chemotherapy cycles) were calculated. RESULTS: Median age was 66 years and mean PSA 171.25 ng/mL. The average number of given cycles was 6.3. A good PSA response (>50% decline) was observed in 26/44 cases (59.1%). A total of 17/44 (38.6%) patients expired with a median overall survival of 62.4 weeks. Patients with a Gleason score less than 7, who received more than four cycles and with a more-than-50% decline in PSA had significantly better survival. Variables like age, baseline PSA and nadir PSA did not significantly affect survival. CONCLUSION: The combination of docetaxel/zoledronic/prednisone is safe and effective in the management of HRPC. Patients with a Gleason score <7, PSA decline >50% and those who receive more than four cycles have significantly better survival.
PMID: 19769656 [PubMed - in process]
Possibly overlooked toxicity labeling, 4mg maximum:
FDA Drug Information That Never Reaches Clinicians
http://content.nejm.org/cgi/content/.../561?query=TOC