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Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance

Nature volume 390, pages 404–407 (1997)Cite this article

Abstract

Acquired drug resistance is a major problem in the treatment of cancer. Of the more than 500,000 annual deaths from cancer in the United States1, many follow the development of resistance to chemotherapy. The emergence of resistance depends in part on the genetic instability, heterogeneity and high mutational rate of tumour cells2. In contrast, endothelial cells are genetically stable, homogenous and have a low mutational rate. Therefore, antiangiogenic therapy directed against a tumour's endothelial cells should, in principle, induce little or no drug resistance. Endostatin3, a potent angiogenesis inhibitor, was administered to mice bearing Lewis lung carcinoma, T241 fibrosarcoma or B16F10 melanoma. Treatment was stopped when tumours had regressed. Tumours were then allowed to re-grow and endostatin therapy was resumed. After 6, 4 or 2 treatment cycles, respectively, no tumours recurred after discontinuation of therapy. These experiments show that drug resistance does not develop in three tumour types treated with a potent angiogenesis inhibitor. An unexpected finding is that repeated cycles of antiangiogenic therapy are followed by prolonged tumour dormancy without further therapy.

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Figure 1: Cycled endostatin therapy of tumours grown in the subcutaneous dorsa of mice.
Figure 2: a, Lewis lung carcinoma at day 40, before endostatin therapy has been resumed in the second treatment cycle.
Figure 3: Representative histology of dormant tumours treated with cycled endostatin and of tumours implanted in the left flank after the original tumour became dormant.
Figure 4: Treatment of Lewis lung carcinoma with cyclophosphamide.

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Acknowledgements

We thank R. Cotran for analysis of the histological sections, E. Flynn for preparation of the histological sections, K. Keough for help with protein purification, L. DeSantis for photography and S. Moscowitz of Advanced Medical Graphics for help with the figures. This study was supported by a grant to the Children's Hospital from EntreMed (Rockville, Maryland) and by NIH grants. T.B. is a recipient of an Erwin-Schrödinger-Stipendium (Fond zur Förderung der Wissenschaftlichen Forschung, Austria). T. Browder is a recipient of an American Cancer Society Career Development Award.

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Authors and Affiliations

  1. Department of Surgery Department of Pediatric Oncology, Departments of Surgery, Dana Farber Cancer Center, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Thomas Boehm, Judah Folkman, Timothy Browder & Michael S. O'Reilly

  2. Division of Hematology-Oncology Department of Pediatric Oncology, Departments of Surgery, Dana Farber Cancer Center, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Timothy Browder

  3. Department of Pediatric Oncology, Departments of Surgery, Children's Hospital, Dana Farber Cancer Center, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Timothy Browder

  4. Cellular Biology, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Judah Folkman

  5. Pediatrics, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Timothy Browder

  6. Joint Center for Radiation Therapy, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Michael S. O'Reilly

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  1. Thomas Boehm
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Correspondence to Thomas Boehm.

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Boehm, T., Folkman, J., Browder, T. et al. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390, 404–407 (1997). https://doi.org/10.1038/37126

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