Polyethylene glycol conjugated insulin-like growth factor binding protein-1 (IGFBP-1) inhibits growth of breast cancer in athymic mice.

Insulin-like growth factor (IGF) binding protein-1 (BP-1) inhibits IGF-mediated proliferation of some breast cancer cell lines in vitro. Here we examined whether recombinant human wild-type IGFBP-1 (WT-BP-1) and IGFBP-1 conjugated with polyethylene glycol (PEG-BP-1) could inhibit breast cancer growth. Three breast cancer cell lines were used: MCF-7, MDA-MB-231 and MDA-MB-435A (ascites model). The cells were grown in agar with or without the BP-1 conjugates to investigate their effect on colony formation. Both WT-BP-1 and PEG-BP-1 inhibited anchorage-independent growth (AIG) of MCF-7 and MDA-MB-435A cells. AIG of MDA-MB-231 cells was not inhibited by PEG-BP-1, whereas WT-BP-1 significantly stimulated colony number. We also tested both forms of BP-1 in xenograft tumour models. Two solid breast tumour models were studied using MCF-7 and MDA-MB-231 cell lines, and one ascites model using the MDA-MB-435A cell line. PEG-BP-1 inhibited malignant ascites formation in the MDA-MB-435A model. Conversely, PEG-BP-1 did not significantly inhibit MCF-7 xenograft growth. However, the MDA-MB-231 tumour growth curves were significantly different by a constant amount, suggesting that PEG-BP-1 treatment inhibited early tumour growth of this cell line. In contrast, WT-BP-1 was ineffective in the MDA-MB-231 tumours. These data show that anti-IGF strategies can be used to inhibit breast cancer cell growth. Since PEG-BP-1 inhibited the in vivo, but not in vitro, growth of MDA-MB-231, we speculate that PEG-BP-1 may block host IGF functions required for optimal tumorigenesis. Because PEG-BP-1 has a prolonged serum half-life compared to WT-BP-1, we conclude that improvements in BP-1 pharmacological properties enhanced its antitumour effects in vivo.

Recombinant human insulin-like growth factor (IGF)-binding protein-1 inhibits somatic growth stimulated by IGF-I and growth hormone in hypophysectomized rats.

We have examined the effects of exogenously administered recombinant human insulin-like growth factor-binding protein-1 (rhIGFBP-1) alone and in combination with recombinant human insulin-like growth factor-I (rhIGF-I) or human GH on weight gain and tibial epiphysis enlargement in hypophysectomized rats. rhIGF-I, given twice daily by sc injection, increased both growth parameters in a dose-dependent manner. Coadministration of increasing amounts of rhIGFBP-1 with a constant amount of rhIGF-I (80 micrograms/injection, given twice daily) resulted in a dose-dependent inhibition of the growth-promoting effects of rhIGF-I. A rhIGFBP-1 dose of 9.8 micrograms/injection (an IGFBP-1/IGF-I molar ratio of 0.04:1) caused no significant effect on rhIGF-I-stimulated growth parameters, whereas a rhIGFBP-1 dose of 1200 micrograms/injection (IGFBP-1/IGF-I molar ratio of 5:1) resulted in 78% or greater inhibition of rhIGF-I-stimulated growth (P < 0.05). rhIGFBP-1 doses of 48 and 240 micrograms/injection (IGFBP-1/IGF-I molar ratios of 0.2:1 and 1:1, respectively) had intermediate inhibitory effects. None of the rhIGFBP-1 doses potentiated the growth-promoting effects of rhIGF-I. Rats treated with rhIGFBP-1 alone (twice daily injections of 9.8, 48, 240, or 1200 micrograms) showed no significant differences in growth parameters compared to rats treated with vehicle. Coadministration of rhIGFBP-1 (1200 micrograms/injection, given twice daily) with GH (15 mU/injection, given twice daily) inhibited weight gain and tibial epiphysis enlargement stimulated by GH by at least 50% in each of two experiments (P < 0.05). These studies demonstrate that nonphosphorylated rhIGFBP-1 can inhibit the growth-promoting effects of rhIGF-I and GH in vivo. The results suggest that in addition to its proposed role in glucose homeostasis, IGFBP-1 may play a role in inhibiting somatic growth and other physiological functions stimulated by IGF-I and GH.