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.

Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer.

BACKGROUND: Tamoxifen, a nonsteroidal estrogen antagonist, is the most prescribed drug for the treatment of breast cancer. The use of tamoxifen is limited, however, by the development of resistance to this compound in most patients. Although tamoxifen behaves primarily as an estrogen antagonist, it has agonist (or growth-stimulatory) activity as well. ICI 182,780 is a 7 alpha-alkylsulfinyl analogue of estradiol lacking agonist activity. The absence of agonist activity may make this steroidal antiestrogen superior to tamoxifen in suppressing tumor cell growth. PURPOSE: We compared the inhibitory effects of ICI 182,780, tamoxifen, and estrogen withdrawal on the growth of established tumors and on tumorigenesis in a model system that uses estrogen-dependent, human MCF-7 breast tumor cells growing in athymic nude mice. We also studied the hormonal responsiveness of tumors that became resistant to the two estrogen antagonists and the effects of these drugs on estrogen-regulated gene expression. METHODS: MCF-7 cells were injected subcutaneously into the flanks of castrated, female nude mice. The effects of repeated doses of tamoxifen and ICI 182,780 (500 micrograms and 5 mg, respectively) on the growth of established tumors (8-10 mm in size) were determined after supplemental estrogen was removed. The effects of antiestrogen treatments on the process of tumorigenesis, in the absence of estrogen supplementation, were determined by initiating drug administration on the same day as tumor cell inoculation. To evaluate the hormonal responsiveness of tumors resistant to tamoxifen and ICI 182,780, 1-mm3 segments of the tumors were transplanted onto the flanks of new recipient mice, which were then treated with estrogen or the antiestrogens--alone or in combination. Tumor growth was monitored by measuring tumor volumes twice a week. Expression of the estrogen-responsive genes, pLIV1 and pS2, in the tumors of treated animals was analyzed using blots of total cellular RNA and complementary DNA probes. RESULTS: Treatment with ICI 182,780 suppressed the growth of established tumors twice as long as treatment with tamoxifen or estrogen withdrawal. Tumorigenesis, in the absence of supplemental estrogen, was delayed to a greater extent in ICI 182,780-treated mice than in tamoxifen-treated mice. ICI 182,780 was found to be more effective than tamoxifen in reducing the expression of estrogen-regulated genes. Most tumors eventually became resistant to ICI 182,780 and grew independently of estrogen. CONCLUSIONS: ICI 182,780 is a more effective estrogen antagonist than tamoxifen in the MCF-7 tumor cell/nude mouse model system.