Combined antiestrogen, antiangiogenic and anti-invasion therapy inhibits primary and metastatic tumor growth in the MMTVneu model of breast cancer

Abstract

Treatments available to women with locally advanced breast cancer are unsatisfactory, since most patients succumb to metastatic spread. Therefore, there is a need to devise novel therapeutic combinations that effectively inhibit metastatization and to test them in animal models of breast cancer showing strong similarities with their human counterpart, including the ability to give rise to metastases. With these considerations in mind, tamoxifen (TAM), 4-hydrotamoxifen (4-HT) or liposome-complexed DNA constructs coding for antiangiogenic/anti-invasion proteins (angiostatin, TIMP-2, IFN-a 1 , sFLT-1) were individually administered to MMTVneu transgenic mice. Significant inhibition of primary tumor growth was obtained with TAM (40% inhibition, P¼0.049), angiostatin (85% inhibition, P¼0.001) and TIMP-2 (60% inhibition, P¼0.015). No lung metastasis was observed in any of these treated mice at 5 months, compared with a rate of 70% in control groups. These observations were the basis for designing a combined treatment with all these compounds. The association of angiostatin, TIMP-2 and TAM was greatly effective at the primary tumor level (90% inhibition, P¼0.01). Moreover, all the mice treated with this association were metastasis free at a time point (6 months) in which seven out of nine control mice were either dead from disseminated cancer or showed lung metastasis. This combined therapy could become an important component of anticancer therapy in humans.

Effects of IL-12 gene therapy on spontaneous transgenic and transplanted breast tumors

“…1C) with previously obtained results using other gene therapy approaches in the same transgenic model [7], along with their respective control groups, indicate that the effects of this naked DNA IL-12 gene therapy protocol were similar to those obtained with anti-angiogenic gene therapy approaches in our hands (Fig. 1E).…”

“…The schedule of IL-12 plasmid injection was every 11 days for a total of eight administrations. Gene therapy approaches for Angiostatin, TIMP-2 and IFNa were administered as described previously [7]. GFPneu cells (10 6 /mouse) were also injected subcutaneously into each flank of SCID/ common gamma chain knock-out mice (15), sorted into IL-12 (eight mice) and control plasmid (seven mice) treated groups after 7 days and treated every 11 days.…”

“…Complete necropsies performed on all mice at 5 months did not reveal any lesions due to collateral effects of therapy upon examination of diverse organs including liver, kidney, spleen, heart, lung, and reproductive tract. In order to evaluate treatment efficacy, tumors were weighed and the two groups were compared and subjected to statistical analysis as previously described in detail [5,7] according to the Annapolis meeting [8] recommendations. In the IL-12 treated groups, the average tumor weight was significantly lower than that of the controls (Fig.…”

Oncolytic Herpes Simplex Virus Vector Therapy of Breast Cancer in C3(1)/SV40 T-antigen Transgenic Mice

“…Other transgenic mouse breast cancer models have also been used to test various therapeutic agents, again, usually before tumor appearance. The MMTV-neu transgenic mouse has been used to test a variety of antiestrogen and antiangiogenic factors (including plasmids encoding angiostatin, endostatin, TIMP-2, sFLT-1, and IFN-a) and combinations of them (64). The combination of tamoxifen with rIL-12 was very effective at preventing carcinoma development in the Her2/neu transgenic mouse (65), likely due again to the antiangiogenic properties of IL-12.…”

Met‐Related Receptor Tyrosine Kinase Ron in Tumor Growth and Metastasis

“…The addition of receptor-targeted drugs to chemotherapeutic agents may also be an effective strategy. For instance, a combination therapy of tamoxifen, angiostatin and TIMP-2 (tissue inhibitor of metalloproteinase-2) administered to mice with breast tumors, the MMTV-neu mice, significantly reduced primary tumor growth (90% inhibition, P=0.01) and metastasis free survival of up to 6 months in the experimental group as compared to 33% in control group, suggesting an overall survival advantage with this combinatorial therapy (Sacco et al, 2003).…”