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Antitumoral and antimetastatic effects of metronomic chemotherapy with cyclophosphamide combined with celecoxib on murine mammary adenocarcinomas

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Abstract

Purpose

Metronomic chemotherapy (MCT) refers to the chronic and equally spaced administration of low doses of different chemotherapy drugs, without extended interruptions. Previously, we demonstrated the antitumor effect of MCT with cyclophosphamide (Cy) in a mouse mammary adenocarcinoma model. Herein, we investigated the therapeutic efficacy of metronomic Cy combined with celecoxib (Cel) in two murine mammary adenocarcinoma models.

Methods

Mice were s.c. challenged with M-234p or M-406 mammary tumors and from day 5 or 8 on, respectively, treated with: (I) no treatment (controls); (II) Cy in the drinking water (25–30 mg/kg body weight/day); (III) Cel (30 mg/kg p.o.), five times/week; (IV) treated as II + III. Mice challenged i.v. with M-234p or M-406 tumor cells received, on day 3, the same treatments.

Results

We found that MCT with Cy plus Cel inhibited tumor growth decreased lung metastases, and increased the median survival time, in both tumor models, having very low toxicity. MCT with Cy combined with Cel was more effective than each monotherapy.

Conclusions

The therapeutic benefits of combined MCT with cyclophosphamide plus celecoxib on mammary adenocarcinomas together with its very low toxicity profile warrant further study in an attempt to make the translation into the clinic.

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References

  • Andre N, Rome A, Coze C, Padovani L, Pasquier E, Camoin L, Gentet JC (2008) Metronomic etoposide/cyclophosphamide/celecoxib regimen given to children and adolescents with refractory cancer: a preliminary monocentric study. Clin Ther 30:1336–1340

    Article  CAS  PubMed  Google Scholar 

  • Barnes NL, Warnberg F, Farnie G, White D, Jiang W, Anderson E, Bundred NJ (2007) Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer. Br J Cancer 96:575–582

    Article  CAS  PubMed  Google Scholar 

  • Basu GD, Pathangey LB, Tinder TL, Lagioia M, Gendler SJ, Mukherjee P (2004) Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer. Mol Cancer Res 2:632–642

    CAS  PubMed  Google Scholar 

  • Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 100:12917–12922

    Article  CAS  PubMed  Google Scholar 

  • Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886

    CAS  PubMed  Google Scholar 

  • Buckstein R, Kerbel RS, Shaked Y, Nayar R, Foden C, Turner R, Lee CR, Taylor D, Zhang L, Man S, Baruchel S, Stempak D et al (2006) High-Dose celecoxib and metronomic “low-dose” cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin’s lymphoma. Clin Cancer Res 12:5190–5198

    Article  CAS  PubMed  Google Scholar 

  • Canadian Council on Animal Care (1993) Guide to the care and use of experimental animals, 2nd edn, vol 2. CCAC, Otawa

  • Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nole F, Peruzzotti G, Robertson C, Orlando L, Cinieri D, De BF, Viale G et al (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13:73–80

    Article  CAS  PubMed  Google Scholar 

  • Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nole F, Viale G, Goldhirsch A (2006) Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 17:232–238

    Article  CAS  PubMed  Google Scholar 

  • Cruz-Munoz W, Man S, Xu P, Kerbel RS (2008) Development of a preclinical model of spontaneous human melanoma central nervous system metastasis. Cancer Res 68:4500–4505

    Article  CAS  PubMed  Google Scholar 

  • DiMasso R, Abdala S, Sanchez S, Font M (1991) Respuesta a la selección divergente por conformación corporal en el ratón. Mendeliana 9:79–92

    Google Scholar 

  • Ding XZ, Tong WG, Adrian TE (2001) Cyclooxygenases and lipoxygenases as potential targets for treatment of pancreatic cancer. Pancreatology 1:291–299

    Article  CAS  PubMed  Google Scholar 

  • Drevs J, Fakler J, Eisele S, Medinger M, Bing G, Esser N, Marme D, Unger C (2004) Antiangiogenic potency of various chemotherapeutic drugs for metronomic chemotherapy. Anticancer Res 24:1759–1763

    CAS  PubMed  Google Scholar 

  • du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel RS (2006) Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. Clin Cancer Res 12:904–916

    Article  CAS  PubMed  Google Scholar 

  • Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368–4380

    Article  CAS  PubMed  Google Scholar 

  • Emmenegger U, Morton GC, Francia G, Shaked Y, Franco M, Weinerman A, Man S, Kerbel RS (2006) Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia. Cancer Res 66:1664–1674

    Article  CAS  PubMed  Google Scholar 

  • Fidler IJ, Ellis LM (2000) Chemotherapeutic drugs—more really is not better. Nat Med 6:500–502

    Article  CAS  PubMed  Google Scholar 

  • Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  CAS  PubMed  Google Scholar 

  • Folkman J (1995) The influence of angiogenesis research on management of patients with breast cancer. Breast Cancer Res Treat 36:109–118

    Article  CAS  PubMed  Google Scholar 

  • Fontana A, Galli L, Fioravanti A, Orlandi P, Galli C, Landi L, Bursi S, Allegrini G, Fontana E, Di Marsico R, Antonuzzo A, D’Arcangelo M, Danesi R, Del Tacca M, Falcone A, Bocci G (2009) Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res 15:4954–4962

    Article  CAS  PubMed  Google Scholar 

  • Gately S, Kerbel R (2003) Therapeutic potential of selective cyclooxygenase-2 inhibitors in the management of tumor angiogenesis. Prog Exp Tumor Res 37:179–192

    Article  CAS  PubMed  Google Scholar 

  • Gately S, Li WW (2004) Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 31:2–11

    Article  CAS  PubMed  Google Scholar 

  • Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R (2003) Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer 98:1643–1648

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Bergers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105:1045–1047

    Article  CAS  PubMed  Google Scholar 

  • Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  CAS  PubMed  Google Scholar 

  • Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436

    Article  CAS  PubMed  Google Scholar 

  • Kesari S, Schiff D, Doherty L, Gigas DC, Batchelor TT, Muzikansky A, O’Neill A, Drappatz J, Chen-Plotkin AS, Ramakrishna N, Weiss SE, Levy B et al (2007) Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults. Neuro Oncol 9:354–363

    Article  CAS  PubMed  Google Scholar 

  • Kieran MW, Turner CD, Rubin JB, Chi SN, Zimmerman MA, Chordas C, Klement G, Laforme A, Gordon A, Thomas A, Neuberg D, Browder T et al (2005) A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol 27:573–581

    Article  PubMed  Google Scholar 

  • Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15–R24

    Article  CAS  PubMed  Google Scholar 

  • Lord R, Nair S, Schache A, Spicer J, Somaihah N, Khoo V, Pandha HJ (2007) Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. Urol 177:2136–2140

    Article  CAS  Google Scholar 

  • Ma J, Waxman DJ (2008) Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. Mol Cancer Ther 7:79–89

    Article  CAS  PubMed  Google Scholar 

  • Maier TJ, Schilling K, Schmidt R, Geisslinger G, Grosch S (2004) Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Biochem Pharmacol 67:1469–1478

    Article  CAS  PubMed  Google Scholar 

  • Mainetti L, Rozados V, Bonfil RD, Scharovsky OG (2005) Metronomic therapy with cyclophosphamide or doxorubicin inhibits mouse mammary adenocarcinoma growth and metastasis development. Proc Am Assoc Cancer Res 46:1377

    Google Scholar 

  • Man S, Bocci G, Francia G, Green SK, Jothy S, Hanahan D, Bohlen P, Hicklin DJ, Bergers G, Kerbel RS (2002) Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62:2731–2735

    CAS  PubMed  Google Scholar 

  • Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311

    CAS  PubMed  Google Scholar 

  • Munoz R, Man S, Shaked Y, Lee CR, Wong J, Francia G, Kerbel RS (2006) Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy. Cancer Res 66:3386–3391

    Article  CAS  PubMed  Google Scholar 

  • Nicolini A, Mancini P, Ferrari P, Anselmi L, Tartarelli G, Bonazzi V, Carpi A, Giardino R (2004) Oral low-dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC). Biomed Pharmacother 58:447–450

    CAS  PubMed  Google Scholar 

  • Ogata Y, Mori S, Ishibashi N, Akagi Y, Ushijima M, Murakami H, Fukushima T, Shirouzu K (2007) Metronomic chemotherapy using weekly low-dosage CPT-11 and UFT as postoperative adjuvant therapy in colorectal cancer at high risk to recurrence. J Exp Clin Cancer Res 26:475–482

    CAS  PubMed  Google Scholar 

  • Orlando L, Cardillo A, Ghisini R, Rocca A, Balduzzi A, Torrisi R, Peruzzotti G, Goldhirsch A, Pietri E, Colleoni M (2006a) Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 6:225

    Article  PubMed  Google Scholar 

  • Orlando L, Cardillo A, Rocca A, Balduzzi A, Ghisini R, Peruzzotti G, Goldhirsch A, D’Alessandro C, Cinieri S, Preda L, Colleoni M (2006b) Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer. Anticancer Drugs 17:961–967

    Article  CAS  PubMed  Google Scholar 

  • Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952

    Article  CAS  PubMed  Google Scholar 

  • Rozados VR, Sanchez AM, Gervasoni SI, Berra HH, Matar P, Scharovsky OG (2004) Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity. Ann Oncol 15:1543–1550

    Article  CAS  PubMed  Google Scholar 

  • Squartini F, Pingitore R (1994) Tumours of the mammary gland. In: Turusov V, Mohr U (eds) Pathology of tumours in laboratory animals. Oxford University Press, New York, pp 47–100

    Google Scholar 

  • Stempak D, Gammon J, Halton J, Moghrabi A, Koren G, Baruchel S (2006) A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. J Pediatr Hematol Oncol 28:720–728

    Article  CAS  PubMed  Google Scholar 

  • Watson J, Chuah SY (1992) Technique for the primary culture of human breast cancer cells and measurement of their prostaglandin secretion. Clin Sci (Lond) 83:347–352

    CAS  Google Scholar 

  • Yap R, Veliceasa D, Emmenegger U, Kerbel RS, McKay LM, Henkin J, Volpert OV (2005) Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy. Clin Cancer Res 11:6678–6685

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful to Dr. M. J. Cisterna and Dr. H. H. Berra for the EKG determinations, to Wiener Lab for providing the reagents for hematological and serological determinations, and to Dr. Eduardo Roggero for his cooperation in the histopathologic analysis. Work in O.G.S. laboratory is supported by grants from National University of Rosario (Argentina). O.G.S. is a member of the scientific career of the Research Council of the National University of Rosario (CIUNR, Argentina).

Conflict of interest statement

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe 3100, 2000, Rosario, Argentina

    Leandro E. Mainetti, Viviana R. Rozados, Ana Rossa & O. Graciela Scharovsky

  2. Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    R. Daniel Bonfil

Authors
  1. Leandro E. Mainetti
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  2. Viviana R. Rozados
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  3. Ana Rossa
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  4. R. Daniel Bonfil
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  5. O. Graciela Scharovsky
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Corresponding author

Correspondence to O. Graciela Scharovsky.

Additional information

The authors L. E. Mainetti and V. R. Rozados contributed equally to this work.

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Mainetti, L.E., Rozados, V.R., Rossa, A. et al. Antitumoral and antimetastatic effects of metronomic chemotherapy with cyclophosphamide combined with celecoxib on murine mammary adenocarcinomas. J Cancer Res Clin Oncol 137, 151–163 (2011). https://doi.org/10.1007/s00432-010-0869-9

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