HER2 Support Group Forums - View Single Post - BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

Rich66 · 06-29-2009, 02:45 PM

Oncology. 2006;70(2):147-53. Epub 2006 Apr 26.
Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin: in vitro isobologram studies with conventional and nonconventional cytotoxic agents.

Budman DR, Calabro A.
Section of Experimental Therapeutics, Don Monti Division of Oncology, North Shore University Hospital, New York University, Manhasset, 11030, USA. budman@nshs.edu

LINK

Abstract

OBJECTIVES: To identify synergistic combinations of clinically available agents with zoledronic acid which would enhance antitumor activity as measured by median effect isobologram analysis and apoptosis assays in vitro.
METHODS: The interaction of zoledronic acid as a doublet with either carboplatin, cisplatin, 5'DFUR, docetaxel, epirubicin, fluvastatin, gemcitabine, imatinib, paclitaxel, trastuzumab, or vinorelbine was studied in a 72-hour in vitro system using defined human cancer cell lines grown as a monolayer in exponential phase. Drug effect on growth was measured by a standard MTT assay. Median effect isobologram analysis was applied to the results to determine the presence of synergism, additive effects, or antagonism of drug combinations. Synergistic combinations were also assayed by a cytoplasmic histone-associated DNA fragmentation apoptosis assay to verify that the effect was not cytostatic.
RESULTS: Zoledronic acid with gemcitabine demonstrated global cytotoxic synergy across 7 of 8 cell lines. Clinically achievable concentrations of fluvastatin with zoledronic acid also demonstrated synergy in 7 of 8 cell lines. All the breast cancer cell lines were sensitive. Zoledronic acid and epirubicin were antagonistic in all 4 breast cell lines studied.
CONCLUSIONS: Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies.

PMID: 16645328 [PubMed - indexed for MEDLINE]

J Clin Immunol. 2010 Sep;30(5):766-74. Epub 2010 Jun 15.
Coculturing dendritic cells with zoledronate acid efficiently enhance the anti-tumor effects of cytokine-induced killer cells.

Su X, Zhang L, Jin L, Ye J, Guan Z, Chen R.
Biomedical Research Center, The First Hospital of Kunming, Kunming 650011, People's Republic of China. suxs163@163.com
LINK

Abstract

INTRODUCTION: Dendritic cells (DCs) have greater stimulating activity on innate and adaptive immunity following short-term sensitization with zoledronate acid (DCs(Zol)). We identified the phenotype, cytotoxicity, and mechanisms of killing of cytokine-induced killer (CIK) cells which were cocultured with DCs(Zol).
METHODS: Adherent and nonadherent cells of peripheral blood mononuclear cell from myeloma patients were incubated for DCs and CIK cells. Then, the CIK cells were cocultured with DCs(Zol) (DCs(Zol)-CIK). Expression of markers for DCs(Zol)-CIK cells was measured using flow cytometry. Cytotoxicity was evaluated by against human myeloma cell lines and mechanisms of killing were tested by selectively blocking NKG2D receptor. The anti-tumor activity of these effector cells was further evaluated using a nude mice tumor model.
RESULTS: gammadelta TCR expression of CIK cells significantly increased after coculture with immature or mature DCs(Zol) (iDCs/mDCs(Zol)-CIK) and these cells aggressively lysed myeloma cells compared with mDCs-CIK and zoledronate acid pulsed CIK cells (CIK(Zol); 50.8 +/- 7.9% and 48.2 +/- 4.7% versus 31.9 +/- 5.1% and 20.5 +/- 3.6%, effector versus target ratio was 60:1). Both alphabeta T and gammadelta T cells in the iDCs(Zol)-CIK cells performed the majority of lysis. The iDCs/mDCs(Zol)-CIK cells greatly increased NKG2D expression compared with mDCs-CIK and CIK(Zol) during culture (71.5 +/- 11.3% and 67.7 +/- 9.3% versus 51.3 +/- 6.2% and 47.1 +/- 5.7%). iDCs(Zol)-CIK cell-mediated lysis dropped 69.21% when the NKG2D receptor was blocked and the cytotoxicity correlated with NKG2D ligand-MICA expression on the target cells. In a human myeloma bearing nude mice model, iDCs(Zol)-CIK and mDCs(Zol)-CIK cells treatment groups obtained 75% and 62.5% long-term survival (>120 days) respectively, as compared with none of the control animals or 37.5% treated with mDCs-CIK cells.
CONCLUSION: Large numbers of CIK cells with greater anti-tumor activities are rapidly generated by Zol-treated iDCs/mDCs. This strategy is worthy of further investigation to improve adoptive cell therapy against tumors.

PMID: 20549316 [PubMed - in process]

06-29-2009, 02:45 PM	#15
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Oncology. 2006;70(2):147-53. Epub 2006 Apr 26. Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin: in vitro isobologram studies with conventional and nonconventional cytotoxic agents. Budman DR, Calabro A. Section of Experimental Therapeutics, Don Monti Division of Oncology, North Shore University Hospital, New York University, Manhasset, 11030, USA. budman@nshs.edu LINK Abstract OBJECTIVES: To identify synergistic combinations of clinically available agents with zoledronic acid which would enhance antitumor activity as measured by median effect isobologram analysis and apoptosis assays in vitro. METHODS: The interaction of zoledronic acid as a doublet with either carboplatin, cisplatin, 5'DFUR, docetaxel, epirubicin, fluvastatin, gemcitabine, imatinib, paclitaxel, trastuzumab, or vinorelbine was studied in a 72-hour in vitro system using defined human cancer cell lines grown as a monolayer in exponential phase. Drug effect on growth was measured by a standard MTT assay. Median effect isobologram analysis was applied to the results to determine the presence of synergism, additive effects, or antagonism of drug combinations. Synergistic combinations were also assayed by a cytoplasmic histone-associated DNA fragmentation apoptosis assay to verify that the effect was not cytostatic. RESULTS: Zoledronic acid with gemcitabine demonstrated global cytotoxic synergy across 7 of 8 cell lines. Clinically achievable concentrations of fluvastatin with zoledronic acid also demonstrated synergy in 7 of 8 cell lines. All the breast cancer cell lines were sensitive. Zoledronic acid and epirubicin were antagonistic in all 4 breast cell lines studied. CONCLUSIONS: Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies. PMID: 16645328 [PubMed - indexed for MEDLINE] J Clin Immunol. 2010 Sep;30(5):766-74. Epub 2010 Jun 15. Coculturing dendritic cells with zoledronate acid efficiently enhance the anti-tumor effects of cytokine-induced killer cells. Su X, Zhang L, Jin L, Ye J, Guan Z, Chen R. Biomedical Research Center, The First Hospital of Kunming, Kunming 650011, People's Republic of China. suxs163@163.com LINK Abstract INTRODUCTION: Dendritic cells (DCs) have greater stimulating activity on innate and adaptive immunity following short-term sensitization with zoledronate acid (DCs(Zol)). We identified the phenotype, cytotoxicity, and mechanisms of killing of cytokine-induced killer (CIK) cells which were cocultured with DCs(Zol). METHODS: Adherent and nonadherent cells of peripheral blood mononuclear cell from myeloma patients were incubated for DCs and CIK cells. Then, the CIK cells were cocultured with DCs(Zol) (DCs(Zol)-CIK). Expression of markers for DCs(Zol)-CIK cells was measured using flow cytometry. Cytotoxicity was evaluated by against human myeloma cell lines and mechanisms of killing were tested by selectively blocking NKG2D receptor. The anti-tumor activity of these effector cells was further evaluated using a nude mice tumor model. RESULTS: gammadelta TCR expression of CIK cells significantly increased after coculture with immature or mature DCs(Zol) (iDCs/mDCs(Zol)-CIK) and these cells aggressively lysed myeloma cells compared with mDCs-CIK and zoledronate acid pulsed CIK cells (CIK(Zol); 50.8 +/- 7.9% and 48.2 +/- 4.7% versus 31.9 +/- 5.1% and 20.5 +/- 3.6%, effector versus target ratio was 60:1). Both alphabeta T and gammadelta T cells in the iDCs(Zol)-CIK cells performed the majority of lysis. The iDCs/mDCs(Zol)-CIK cells greatly increased NKG2D expression compared with mDCs-CIK and CIK(Zol) during culture (71.5 +/- 11.3% and 67.7 +/- 9.3% versus 51.3 +/- 6.2% and 47.1 +/- 5.7%). iDCs(Zol)-CIK cell-mediated lysis dropped 69.21% when the NKG2D receptor was blocked and the cytotoxicity correlated with NKG2D ligand-MICA expression on the target cells. In a human myeloma bearing nude mice model, iDCs(Zol)-CIK and mDCs(Zol)-CIK cells treatment groups obtained 75% and 62.5% long-term survival (>120 days) respectively, as compared with none of the control animals or 37.5% treated with mDCs-CIK cells. CONCLUSION: Large numbers of CIK cells with greater anti-tumor activities are rapidly generated by Zol-treated iDCs/mDCs. This strategy is worthy of further investigation to improve adoptive cell therapy against tumors. PMID: 20549316 [PubMed - in process]