Skip to main content
SpringerLink
Log in

Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

The ability of the antiangiogenic agents TNP-470 and minocycline, singly or in combination, to potentiate the antitumor effects of several cytotoxic therapies was assessed in the murine EMT-6 mammary carcinoma as well as in two drug resistant sublines of that tumor designated EMT-6/CTX and EMT-6/CDDP.

The antiangiogenic agents alone or in combination did not alter the growth of the tumors. However, their administration along with cyclophosphamide, CDDP, or thiotepa substantially increased the tumor growth delay produced by these cytotoxic therapies in tumors responsive to the drugs — the increase was about 2-fold for TNP-470 and minocycline together. In drug resistant tumors, treatment with the antiangiogenic agents did not reverse drug resistance but did increase the effect of the cytotoxic drugs.

Treatment with TNP-470/minocycline also increased the oxygenation of each of the three tumors. Thus, TNP-470/minocycline administration increased the efficacy of fractionated radiation therapy, especially when used along with a perflubron emulsion oxygen delivery agent/carbogen.

These results indicate that treatment regimens including therapies directed toward the proliferating normal cells within a tumor mass as well as therapies directed toward the malignant cells can produce improved outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Connolly JL, Ducatman BS, Schnitt SJ, Dvorak AM, Dvorak HF: Principles of cancer pathology.In: Holland JF, Frei E III, Bast RC Jr, Kufe DW, Morton DL, Weichselbaum RR (eds) Cancer Medicine. Lea & Febiger, Philadelphia PA, 1993, pp 432–450

    Google Scholar 

  2. Alvarez Sotomayor E, Teicher BA, Schwartz GN, Holden SA, Menon K, Herman TS, Frei E III: Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo. Cancer Chemother Pharmacol 30:377–384, 1992

    Google Scholar 

  3. Teicher BA, Alvarez Sotomayor E, Huang ZD: Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res 52:6702–6704, 1992

    Google Scholar 

  4. Teicher BA, Alvarez Sotomayor E, Huang ZD, Ara G, Holden S, Khandekar V, Chen Y-N: β-cyclodextrin tetradecasulfate/tetrahydro-cortisol ± minocycline as modulators of cancer therapies in vitro and in vivo against primary and metastatic Lewis lung carcinoma. Cancer Chemother Pharmacol 33:229–38, 1993

    Google Scholar 

  5. Teicher BA, Holden SA, Ara G, Alvarez Sotomayor E, Huang ZD, Chen Y-N, Brem H: Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other antiangiogenic agents. Int J Cancer 57:920–925, 1994

    Google Scholar 

  6. Brem H, Ingber D, Blood CH, Bradley D, Urioste S, Folkman J: Suppression of tumor metastasis by angiogenesis inhibition. Surg Forum 42:439, 1991

    Google Scholar 

  7. Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J: Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348:555–557, 1990

    Google Scholar 

  8. Kusaka M, Sudo K, Matsutani E, Kozai Y, Marui S, Fujita T, Ingber D, Folkman J: Cytostatic inhibition of endothelial cell growth by the angiogenesis inhibitor TNP-470 (AGM-1470). Br J Cancer 69:212–216, 1994

    Google Scholar 

  9. Antoine N, Greimers R, De Roanne C, Kusaka M, Heinen E, Simar LJ, Castronovo V: AGM-1470, a potent angiogenesis inhibitor, prevents the entry of normal but not transformed endothelial cells into the G1 phase of the cell cycle. Cancer Res 54:2073–2076, 1994

    Google Scholar 

  10. Yamamoto T, Sudo K, Fujita T: Significant inhibition of endothelial cell growth in tumor vasculature by an angiogenesis inhibitor, TNP-470 (AGM-1470). Anticancer Res 14:1–4, 1994

    Google Scholar 

  11. Kusaka M, Sudo K, Fujita T, Marui S, Itoh F, Ingber D, Folkman J: Potent anti-angiogenic action of AGM-1470: comparison to the fumagillin parent. Biochim Biophys Res Commun 174:1070–1076, 1991

    Google Scholar 

  12. Tamargo RJ, Bok RA, Brem H: Angiogenesis inhibition by minocycline. Cancer Res 51:672–675, 1991

    Google Scholar 

  13. Riess JG: Reassessment of criteria for the selection of perfluorochemicals for second-generation blood substitutes: analysis of structure/property relationships. Artif Organs 8:44–56, 1984

    Google Scholar 

  14. Teicher BA, Herman TS, Holden SA, Wang Y, Pfeffer MR, Crawford JM, Frei E III: Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 247:1457–1461, 1990

    Google Scholar 

  15. Teicher BA, Chatterjee D, Liu J-T, Holden SA, Ara G: Protection of bone-marrow granulocyte-macrophage colony-forming units in mice bearing in vivo alkylating-agent-resistant EMT-6 tumors. Cancer Chemother Pharmacol 32:315–319, 1993

    Google Scholar 

  16. Chatterjee D, Liu CI-T, Northey D, Teicher BA: Molecular characterization of the in vivo alkylating agent resistant murine EMT-6 mammary carcinoma tumors. Cancer Chemother Pharmacol, in press

  17. Teicher BA, Dupuis NP, Kusumoto T, Liu M, Liu F, Menon K, Schwartz GN, Frei E III: Decreased tumor oxygenation after cyclophosphamide reoxygenation and therapeutic enhancement with a perflubron emulsion/carbogen breathing. Int J Oncol 3:197–203, 1993

    Google Scholar 

  18. Teicher BA, Schwartz GN, Alvarez Sotomayor E, Robinson MF, Dupuis NP, Menon K: Oxygenation of tumors by a hemoglobin solution. J Cancer Res Clin Oncol 120:85–90, 1993

    Google Scholar 

  19. Teicher BA, Holden SA, Dupuis NP, Kusumoto T, Liu M, Liu F, Menon K: Oxygenation of the rat 9L gliosarcoma and the rat 13762 mammary carcinoma with various doses of a hemoglobin solution. Artif Cells, Blood Substit, & Immobil Biotech 22:827–833, 1994

    Google Scholar 

  20. Teicher BA, Dupuis NP, Holden SA, Schwartz GN, Lester S, Frei E III: Definition and manipulation of tumor oxygenation. Radiat Oncol Invest 2:66–76, 1994

    Google Scholar 

  21. Teicher BA, Waxman DJ, Holden SA, Wang Y, Clarke L, Alvarez Sotomayor E, Jones SM, Frei E III: Evidence for enzymatic activation and oxygen involvement in cytotoxicity and antitumor activity of N,N′,N”-triethylenethiophosphoramide. Cancer Res 49:4996–5001, 1989

    Google Scholar 

  22. Folkman J: What is the role of angiogenesis in metastasis from cutaneous melanoma? Eur J Cancer Clin Oncol 23:361–363, 1987

    Google Scholar 

  23. Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6, 1990

    Google Scholar 

  24. Folkman J, Ingber DE: Angiostatic steroids: method of discovery and mechanism of action. Ann Surg 206:374–383, 1987

    Google Scholar 

  25. Folkman J, Klagsbrun M: Angiogenic factors. Science 235:442–447, 1987

    Google Scholar 

  26. Folkman J, Langer R, Lingardt R, Haudenschild C, Taylor S: Angiogenesis inhibition and tumour regression caused by heparin or a heparin fragment in the presence of cortisone. Science 221:719–725, 1983

    Google Scholar 

  27. Folkman J, Watson K, Ingber D, Hanahan D: Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61, 1989

    Google Scholar 

  28. Ingber DE, Madri JA, Folkman J: A possible mechanism for inhibition of angiogenesis by angiostatic steroids: induction of capillary basement membrane dissolution. Endocrinology 119:1768–1775, 1986

    Google Scholar 

  29. Willis RA: Pathology of Tumors. Butterworth & Co., Ltd., London, 1953.

    Google Scholar 

  30. Rubin P, Casarett G: Microcirculation of tumors, part I: anatomy, function and necrosis. Clin Radiol 17:220–229, 1966

    Google Scholar 

  31. Weidner N, Semple JP, Welch WR, Folkman J: Tumor angiogenesis and metastasis — correlation in invasive breast carcinoma. N Engl J Med 324:1–8, 1991

    Google Scholar 

  32. Grunt TW, Lametschwadtner A, Karrer K, Staindl O: The angioarchitecture of the Lewis lung carcinoma in laboratory mice. Scan Electron Microsc 11:557–574, 1986

    Google Scholar 

  33. Grunt TW, Lametschwadtner A, Kerrer K: The characteristic structural feature of the blood vessels of the Lewis lung carcinoma. Scan Electron Microsc 11:575–589, 1986

    Google Scholar 

  34. Chaplin DJ, Durand RE, Olive PL: Acute hypoxia in tumors: implications for modifiers of radiation effects. Int J Radiat Oncol Biol Phys 12:1279–1282, 1986

    Google Scholar 

  35. Senger DR, Van De Water L, Brown LF, Nagy JA, Yeo K-T, Yeo T-K, Berse B, Jackman RW, Dvorak AM, Dvorak HF: Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Met Rev 12:303–324, 1993

    Google Scholar 

  36. Roberts WG, Hasan T: Tumor-secreted vascular permeability factor/vascular endothelial growth factor influences photosensitizer uptake. Cancer Res 53:153–157, 1993

    Google Scholar 

  37. Teicher BA, Rose CM: Perfluorochemical emulsions can increase tumor radiosensitivity. Science 223:934–936, 1984

    Google Scholar 

  38. Teicher BA, Herman TS, Jones SM: Optimization of perfluorochemical levels with radiation therapy in mice. Cancer Res 49:2693–2697, 1989

    Google Scholar 

  39. Teicher BA, Rose CM: Oxygen-carrying perfluorochemical emulsion as an adjuvant to radiation therapy in mice. Cancer Res 44:4285–4288, 1984

    Google Scholar 

  40. Teicher BA, Herman TS, Holden SA, Liu S, Menon K: Effect of dose, schedule and rate administration on radiosensitization by a perfluorooctylbromide emulsion/carbogen. Radiat Oncol Invest 1:14–19, 1993

    Google Scholar 

  41. Teicher BA, Holden SA, Ara G, Ha CS, Herman TS, Northey D: A new concentrated perfluorochemical emulsion and carbogen breathing as a adjuvant to treatment with antitumor alkylating agents. J Cancer Res Clin Oncol 118:509–514, 1992

    Google Scholar 

  42. Holden SA, Teicher BA, Ha C, Ara G, Herman TS: Enhancement by perflubron emulsion (Oxygent®) and carbogen breathing of the tumor growth delay of the FSaIIC fibrosarcoma after treatment with antitumor alkylating agents. Biomat, Artif Cells, Immobil Biotech 20:895–898, 1992

    Google Scholar 

  43. Teicher BA, Herman TS, Menon K: Enhancement of fractionated radiation therapy by an experimental concentrated perflubron emulsion (Oxygent®) in the Lewis lung carcinoma. Biomat, Artif Cells, Immobil Biotech 20:899–902, 1992

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, 44 Binney Street, 02115, Boston, MA, USA

    Beverly A. Teicher, Sylvia A. Holden, Norman P. Dupuis, Yoshihiro Kakeji, Masahiko Ikebe, Yasunori Emi & Donna Goff

Authors
  1. Beverly A. Teicher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylvia A. Holden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Norman P. Dupuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshihiro Kakeji
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masahiko Ikebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasunori Emi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Donna Goff
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Teicher, B.A., Holden, S.A., Dupuis, N.P. et al. Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma. Breast Cancer Res Tr 36, 227–236 (1995). https://doi.org/10.1007/BF00666043

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00666043

Key words

Search

Navigation