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Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases [A. A. B., V. A. B., D. L.], and Laboratory of Pathology, Division of Clinical Sciences, National Cancer Institute [M. T., V. P.], NIH, Bethesda, Maryland 20892-1770, and Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 [T. L. W.]
The insulin-like growth factors (IGF) I and II regulate metabolism, mitogenesis, differentiation, and apoptosis. The therapeutic uses of IGF-I have been discussed extensively; however, excessive activity of the IGF ligands and IGF-I receptor has been suggested as a factor in tumorigenesis. The inhibition of apoptosis by IGF-I is believed to be particularly important for the stimulation of tumor growth. This study examined whether systemic recombinant human IGF-I (rhIGF-I) therapy affects the growth of fibrosarcomas derived from fibroblasts expressing the IGF-I receptor at high or naturally occurring densities (1.9 x 105 compared with 1.6 x 104 IGF-I receptors/cell) in athymic nude mice. Treatment with 4 or 10 mg/kg rhIGF-I resulted in a marked reduction in the tumor latency and stimulated the growth of fibrosarcomas that overexpressed the IGF-I receptor. The latency and growth of fibrosarcomas expressing parental levels of the IGF-I receptor were not affected by rhIGF-I therapy. Analysis of mitosis by histone H3 mRNA in situ hybridization and of apoptosis by terminal deoxynucleotidyl transferase-mediated nick end labeling assay indicated that rhIGF-I-stimulated tumor growth was associated with a marked increase in mitogenesis; however, there was no evidence for any significant effect on apoptosis. These data imply that: (a) systemic rhIGF-I can stimulate the growth of tumors directly by stimulating mitosis; and (b) a reasonable level of IGF-I receptor expression is required for stimulation of tumor growth by systemic rhIGF-I.
1 Funding for this study was provided by Genentech, Inc. (S. San Francisco, CA).
2 To whom requests for reprints should be addressed, at Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Building 10, Room 8S235A, 10 Center Drive, MSC 1770, Bethesda, MD 20892-1770. Phone: (301) 496-8090; Fax: (301) 480-4386; E-mail: Derek@helix.nih.gov.
Received 2/23/98. Accepted 5/13/98.
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