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Preclinical combination therapy of the investigational drug NAMI-A+ with doxorubicin for mammary cancer

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Summary

Aim of the study The tumor metastases targeting ruthenium complex NAMI-A synergistically improves the activity of gemcitabine in combination therapies. High-throughput screening was used to identify other potential drug combinations from a library of FDA approved drugs. Doxorubicin was identified as a hit compound and was therefore evaluated in combination with NAMI-A in vitro and in a preclinical in vivo model. Results High-throughput screening identified eight structurally diverse compounds that synergize with NAMI-A including doxorubicin. The combination index on MCF-7 cells showed synergism as the concentration of NAMI-A increases independent of the doxorubicin concentration. In MCa mammary carcinoma of CBA mice, NAMI-A (35 mg/kg/day i.p. on days 7–12) followed by doxorubicin (10 mg/kg i.p. on day 16), significantly increased the effects of the individual drugs on metastases with 70 % animals resulting free of macroscopically detectable tumor nodules in the lungs at sacrifice. NAMI-A, unlike doxorubicin, cured 60 % of the treated mice but the combination therapy was toxic to the animals. Conclusions The combined therapy of NAMI-A with doxorubicin synergizes on lung metastasis in a preclinical mouse model. The combination therapy at the maximum tolerated doses of the two drugs is toxic. Hence, this combination is not suitable for clinical studies using maximum tolerated doses.

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References

  1. Bergamo A, Gaiddon C, Schellens JHM, Beijnen JH, Sava G (2012) Approaching tumour therapy beyond platinum drugs. Status of the art and perspectives of ruthenium drug candidates. J Inorg Biochem 106:90–99

    Article  CAS  PubMed  Google Scholar 

  2. Romero-Canelon I, Sadler PJ (2013) Next-generation metal anticancer complexes: multitargeting via redox modulation. Inorg Chem 52:12276–12291

    Article  CAS  PubMed  Google Scholar 

  3. Komeda S, Casini A (2012) Next-generation anticancer metallodrugs. Curr Top Med Chem 12:219–235

    Article  CAS  PubMed  Google Scholar 

  4. Sava G, Pacor S, Mestroni G, Alessio E (1992) Na[trans-RuCl4(DMSO)Im], a metal complex of ruthenium with antimetastatic properties. Clin Exp Metastasis 10:273–280

    Article  CAS  PubMed  Google Scholar 

  5. Sava G, Capozzi I, Clerici K, Gagliardi R, Alessio E, Mestroni G (1998) Pharmacological control of lung metastases of solid tumours by a novel ruthenium complex. Clin Exp Metastasis 16:371–379

    Article  CAS  PubMed  Google Scholar 

  6. Sava G, Zorzet S, Turrin C, Vita F, Soranzo MR, Cocchietto M, Bergamo A, DiGiovine S, Pezzoni G, Sartor L, Garbisa S (2003) Dual action of NAMI-A in inhibition of solid tumor metastasis: selective targeting of metastatic cells and binding to collagen. Clin Cancer Res 9:1898–1905

    CAS  PubMed  Google Scholar 

  7. Sava G, Gagliardi R, Bergamo A, Alessio E, Mestroni G (1999) Treatment of metastases of solid mouse tumours by NAMI-A: comparison with cisplatin, cyclophosphamide and dacarbazine. Anticancer Res 19:969–972

    CAS  PubMed  Google Scholar 

  8. Bergamo A, Gagliardi R, Scarcia V, Furlani A, Alessio E, Mestroni G, Sava G (1999) In vitro cell cycle arrest, in vivo action on solid metastasizing tumors, and host toxicity of the antimetastatic drug NAMI-A and cisplatin. J Pharmacol Exp Ther 289:559–564

    CAS  PubMed  Google Scholar 

  9. Gava B, Zorzet S, Spessotto P, Cocchietto M, Sava G (2006) Inhibition of B16 melanoma metastases with the ruthenium complex imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate and down-regulation of tumor cell invasion. J Pharmacol Exp Ther 317:284–291

    Article  CAS  PubMed  Google Scholar 

  10. Bergamo A, Delfino R, Casarsa C, Sava G (2012) Hyperphosphorylation maintenance drives the time-course of G2-M cell cycle arrest after short treatment with NAMI-A in KB cells. Anti Cancer Agents Med Chem 12:949–958

    Article  CAS  Google Scholar 

  11. Fisher B, Bauer M, Wickerham DL, Redmond CK, Fisher ER, Cruz AB, Foster R, Gardner B, Lerner H, Margolese R (1983) Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer: an NSABP update. Cancer 52:1551–1557

    Article  CAS  PubMed  Google Scholar 

  12. Kim T, Giuliano AE, Lyman GH (2006) Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: a metaanalysis. Cancer 106:4–16

    Article  PubMed  Google Scholar 

  13. Fontain DB, van de Water W, Mieog JS, Liefers GJ, van de Velde CJ (2013) Timing of the sentinel lymph node biopsy in breast cancer patients receiving neoadjuvant therapy - recommendations for clinical guidance. Eur J Surg Oncol 39:417–424

    Article  Google Scholar 

  14. Adjuvant systemic therapy for women with node-positive breast cancer. The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. CMAJ 1998,158 Suppl 3:S52-64.

  15. Rademaker-Lakhai JM, van den Bongard D, Pluim D, Beijnen JH, Schellens JH (2004) A Phase I and pharmacological study with imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a novel ruthenium anticancer agent. Clin Cancer Res 10:3717–3727

    Article  CAS  PubMed  Google Scholar 

  16. Leijen S. Phase I/II Study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy. In: Development of combination Therapy with anticancer drugs. PhD Thesis 2013, Gildeprint Drukkerijen, The Netherlands, pp. 274–336.

  17. Gao G, Jiang J, Liang X, Zhou X, Huang R, Chu Z, Zhan Q (2009) A meta-analysis of platinum plus gemcitabine or vinorelbine in the treatment of advanced non-small-cell lung cancer. Lung Cancer 65:339–344

    Article  PubMed  Google Scholar 

  18. Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N (2001) A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer. Health Technol Assess 5:1–195

    Article  Google Scholar 

  19. de Castria TB, da Silva EM, Gois AF, Riera R (2013) Cisplatin versus carboplatin in combination with third-generation drugs for advanced non-small cell lung cancer. Cochrane Database Syst Rev 8:CD009256

    PubMed  Google Scholar 

  20. Matsumoto M, Takeda Y, Maki H, Tojo K, Wada T, Nishitani Y, Maekawa R, Yoshioka T (2001) Preclinical in vivo antitumor efficacy of nedaplatin with gemcitabine against human lung cancer. Jpn J Cancer Res 92:51–58

    Article  CAS  PubMed  Google Scholar 

  21. Giovannetti E, Mey V, Nannizzi S, Barsanti G, Savarino G, Ricciardi S, Del Tacca M, Danesi R (2007) Cytotoxic activity of gemcitabine and correlation with expression profile of drug-related genes in human lymphoid cells. Pharmacol Res 55:343–349

    Article  CAS  PubMed  Google Scholar 

  22. Pacor S, Zorzet S, Cocchietto M, Bacac M, Vadori M, Turrin C, Gava B, Castellarin A, Sava G (2004) Intra-tumoral nami-a treatment triggers metastasis reduction, which correlates to cd44 regulation and til recruitment. J Pharmacol Exp Ther 310:737–744

    Article  CAS  PubMed  Google Scholar 

  23. Coluccia M, Sava G, Salerno G, Bergamo A, Pacor S, Mestroni G, Alessio E (1995) Efficacy of 5-FU combined to Na[trans-RuCl4(DMSO)Im], a novel selective antimetastatic agent, on the survival time of mice with P388 leukemia, P388/DDP subline and MCa mammary carcinoma. Metal-Based Drugs 2:195–199

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Khalaila I, Bergamo A, Bussy F, Sava G, Dyson PJ (2006) The role of cisplatin and NAMI-A plasma-protein interactions in relation to combination therapy. Int J Oncol 29:261–268

    CAS  PubMed  Google Scholar 

  25. Therasse P, Mauriac L, Welnicka-Jaskiewicz M, Bruning P, Cufer T, Bonnefoi H, Tomiak E, Prichard KI, Hamilton A, Piccart MJ (2003) Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol 21:843–850

    Article  CAS  PubMed  Google Scholar 

  26. Mestroni G, Alessio E, Sava G. Nerw salts of anionic complexex of Ru(III), as antimetastatic and antineoplastic agents. PCT. C 07 F 15/00, A61K 31/28. WO 98/00431 08.01.98.

  27. Zhang JH, Chung TD, Oldenburg KR (1999) A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 4:67–73

    Article  PubMed  Google Scholar 

  28. Mosman T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  Google Scholar 

  29. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48:598–601

    Google Scholar 

  30. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55

    Article  CAS  Google Scholar 

  31. Chou TC (1991) The median-effect principle and the combination index for quantitation of synergism and antagonism. In: Chou TC, Rideout DC (eds) Synergism and antagonism in chemotherapy. Academic, San Diego, pp 61–102

    Google Scholar 

  32. Chou TC, Tan QH, Sirontak FM (1993) Quantitation of the synergistic interaction of edatrexate and cisplatin in vitro. Cancer Chemother Pharmacol 31:259–264

    Article  CAS  PubMed  Google Scholar 

  33. Poliak-Blazi M, Boranic M, Marzan B, Radacic M (1981) A transplantable aplastic mammary carcinoma of CBA mice. Vet Arh 51:382–385

    Google Scholar 

  34. Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ, Double JA, Everitt J, Farningham DAH, Glennie MJ, Kelland LR, Robinson V, Stratford IJ, Tozer GM, Watson S, Wedge SR, Eccles SA (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Rapozzi V, Zorzet S, Comelli M, Mavelli I, Perissin L, Giraldi T (1998) Melatonin decreases bone marrow and lymphatic toxicity of Adriamycin in mice bearing TLX5 lymphoma. Life Sci 63:1701–1713

    Article  CAS  PubMed  Google Scholar 

  36. Dethlefsen LA, Riley RM, Roti JL (1979) Flow cytometric analysis of adriamycin-perturbed mouse mammary tumors. J Histochem Cytochem 27:463–469

    Article  CAS  PubMed  Google Scholar 

  37. Cocchietto M, Salerno G, Alessio E, Mestroni G, Sava G (2000) Fate of the antimetastatic ruthenium complex ImH[trans-RuCl4(DMSO)Im] after acute i.v. treatment in mice. Anticancer Res 20:197–202

    CAS  PubMed  Google Scholar 

  38. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gerwirtz DA (1994) Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol 45:649–656

    CAS  PubMed  Google Scholar 

  39. Hudis C (1997) Sequential dose-dense adjuvant therapy with doxorubicin, paclitaxel and cyclophosphamide. Oncology 11:15–18

    CAS  PubMed  Google Scholar 

  40. Mendes F, Groessl M, Nazarov AA, Tsybin YO, Sava G, Santos I (2011) PJ Dyson, Casini A. Metal-based inhibition of poly(ADP-ribose) polymerase – the guardian angel of DNA. J Med Chem 54:2196–2206

    Article  CAS  PubMed  Google Scholar 

  41. Kaun C, Zhang J, Honbo N, Kaileimer JS (2010) Doxorubicin cariomyopathy. Cardiology 115:155–160

    Article  Google Scholar 

  42. Pillozzi Y, Stefanini S, Ristori M, D’Amico M, Alessio E, Scaletti F, Arcangeli A, Messori L. NAMI-A is highly cytotoxic toward various leukaemia cell lines. Angewandte Chemie Int Ed., 2014, in press.

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Acknowledgments

Contributions by Ms. L. Macrì and Mr. G. Flego are gratefully appreciated. Dr. G. Turcatti at the Biomolecular Screening Facility (EPFL), Dr. C. Casarsa who performed the histological examinations and Dr. M. Cocchietto who determined ruthenium content are thanked for their help.

Financial support by: Callerio Foundation Onlus and Swiss National Science Foundation, National Centre of Competence in Research Chemical Biology2Visualisation and Control of Biological Processes Using Chemistry.

Conflict of Interest

No conflict of interest are declared by the authors.

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Authors and Affiliations

  1. Callerio Foundation Onlus, via A. Fleming 22-31/b, 34127, Trieste, Italy

    Alberta Bergamo & Gianni Sava

  2. Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology Lausanne (EPFL), 1015, Lausanne, Switzerland

    Tina Riedel & Paul J. Dyson

  3. Department of Life Sciences, University of Trieste, via A. Fleming 22, 34127, Trieste, Italy

    Gianni Sava

Authors
  1. Alberta Bergamo
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  2. Tina Riedel
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  4. Gianni Sava
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Correspondence to Gianni Sava.

Additional information

+ NAMI-A = the imidazolium trans-[tetrachloro(dimethylsulfoxide)(imidazole)ruthenate(III)]

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Bergamo, A., Riedel, T., Dyson, P.J. et al. Preclinical combination therapy of the investigational drug NAMI-A+ with doxorubicin for mammary cancer. Invest New Drugs 33, 53–63 (2015). https://doi.org/10.1007/s10637-014-0175-5

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  • DOI: https://doi.org/10.1007/s10637-014-0175-5

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