Stimulation of tumor growth by recombinant human insulin-like growth factor-I (IGF-I) is dependent on the dose and the level of IGF-I receptor expression.
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 10(5) compared with 1.6 x 10(4) 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.
Butler
A A
AA
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-1770, USA.
Blakesley
V A
VA
Poulaki
V
V
Tsokos
M
M
Wood
T L
TL
LeRoith
D
D
Pouliki
V
V
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D004273:DNA, Neoplasm / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D004273:DNA, Neoplasm; D006657:Histones; D009363:Neoplasm Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1