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Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models.

Cicatiello V, Apicella I, Tudisco L, Tarallo V, Formisano L, Sandomenico A, Kim Y, Bastos-Carvalho A, Orlandi A, Ambati J, Ruvo M, Bianco R, De Falco S - Oncotarget (2015)

Bottom Line: Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein.Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection.Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.

View Article: PubMed Central - PubMed

Affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics "Adriano Buzzati-Traverso" - CNR, Naples, Italy.

ABSTRACT
To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.

No MeSH data available.


Related in: MedlinePlus

iVR1 showed a synergic effect in combination with irinotecan(A), iVR1 (25 mg/kg, each other day) and irinotecan (50 mg/kg once at week) were delivered alone or in combination starting at day 5 from cell inoculation and for 24 days. TV was measured three times a week and data are represented as the mean ± SEM (N = 7). At day 21: *p < 0.005 for iVR1 and irinotecan compared to vehicle, §p < 0.0001 versus vehicle, #p < 0.005 vs iVR1 and irinotecan. (B), top, western blot analysis of VEGFR1 phosphorylation performed on mixed matching amounts of protein extracts belonging to the same experimental tumor group. Low, normalization with anti-VEGFR1 antibody performed on the same filter. The values of densitometry analyses are shown. Values (in percentages) were calculated as the ratio of degree of receptor phosphorylation with respect to the total receptor amounts. The value of 100 has been arbitrarily assigned to vehicle. (C), Kaplan-Meier survival curves of iVR1, irinorecan and bevacizumab (bevaciz, 5 mg/Kg two times a week) treatments, alone or in combination. Drugs were delivered as in A. Dashed line indicates 50% of survival. Bevaciz, irinotecan or iVR1 treatments were significantly lower compared to vehicle (p < 0.01) as well as the two combination treatments, iVR1 plus irinotecan and bevaciz plus irinotecan (p < 0.001).
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Figure 6: iVR1 showed a synergic effect in combination with irinotecan(A), iVR1 (25 mg/kg, each other day) and irinotecan (50 mg/kg once at week) were delivered alone or in combination starting at day 5 from cell inoculation and for 24 days. TV was measured three times a week and data are represented as the mean ± SEM (N = 7). At day 21: *p < 0.005 for iVR1 and irinotecan compared to vehicle, §p < 0.0001 versus vehicle, #p < 0.005 vs iVR1 and irinotecan. (B), top, western blot analysis of VEGFR1 phosphorylation performed on mixed matching amounts of protein extracts belonging to the same experimental tumor group. Low, normalization with anti-VEGFR1 antibody performed on the same filter. The values of densitometry analyses are shown. Values (in percentages) were calculated as the ratio of degree of receptor phosphorylation with respect to the total receptor amounts. The value of 100 has been arbitrarily assigned to vehicle. (C), Kaplan-Meier survival curves of iVR1, irinorecan and bevacizumab (bevaciz, 5 mg/Kg two times a week) treatments, alone or in combination. Drugs were delivered as in A. Dashed line indicates 50% of survival. Bevaciz, irinotecan or iVR1 treatments were significantly lower compared to vehicle (p < 0.01) as well as the two combination treatments, iVR1 plus irinotecan and bevaciz plus irinotecan (p < 0.001).

Mentions: Among systemic treatments clinically approved for mCRC patients, irinotecan and bevacizumab containing regimens are largely used for their efficacy. Therefore, we evaluated if iVR1 activity might synergize with irinotecan, a camptotecin-based inhibitor of topoisomerase I [32]. Drugs were delivered starting at day 5 from cells inoculation and the combination treatment was compared to single treatments or vehicle (Figure 6A). At day 21 from cell inoculation, tumor growth inhibition induced by iVR1 was similar to that induced by irinotecan and both were significantly greater compared to vehicle (−58.3%, p < 0.005). Strikingly, the iVR1-irinotecan combination induced a very powerful inhibition of tumor growth already at day 21 (−82.1%, p < 0.0001 versus vehicle and −58.2%, p < 0.005, versus iVR1 and irinotecan alone), causing a progressive reduction of the tumors volume starting at day 16. Since we observed an almost total regression of tumors in the combination group, treatments were stopped seven days later. Indeed, at day 28, only two out of seven tumors were still detectable and for the next 20 days tumors were not measurable, with a delay in tumor relapse of about 50 days compared to vehicle-treated tumors. iVR1-treated tumors relapsed more rapidly than the irinotecan-treated ones, both reaching 1500 – 1600 mm3 average volume 20 and 30 days later, respectively, than vehicle-treated tumors (Figure 6A).


Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models.

Cicatiello V, Apicella I, Tudisco L, Tarallo V, Formisano L, Sandomenico A, Kim Y, Bastos-Carvalho A, Orlandi A, Ambati J, Ruvo M, Bianco R, De Falco S - Oncotarget (2015)

iVR1 showed a synergic effect in combination with irinotecan(A), iVR1 (25 mg/kg, each other day) and irinotecan (50 mg/kg once at week) were delivered alone or in combination starting at day 5 from cell inoculation and for 24 days. TV was measured three times a week and data are represented as the mean ± SEM (N = 7). At day 21: *p < 0.005 for iVR1 and irinotecan compared to vehicle, §p < 0.0001 versus vehicle, #p < 0.005 vs iVR1 and irinotecan. (B), top, western blot analysis of VEGFR1 phosphorylation performed on mixed matching amounts of protein extracts belonging to the same experimental tumor group. Low, normalization with anti-VEGFR1 antibody performed on the same filter. The values of densitometry analyses are shown. Values (in percentages) were calculated as the ratio of degree of receptor phosphorylation with respect to the total receptor amounts. The value of 100 has been arbitrarily assigned to vehicle. (C), Kaplan-Meier survival curves of iVR1, irinorecan and bevacizumab (bevaciz, 5 mg/Kg two times a week) treatments, alone or in combination. Drugs were delivered as in A. Dashed line indicates 50% of survival. Bevaciz, irinotecan or iVR1 treatments were significantly lower compared to vehicle (p < 0.01) as well as the two combination treatments, iVR1 plus irinotecan and bevaciz plus irinotecan (p < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: iVR1 showed a synergic effect in combination with irinotecan(A), iVR1 (25 mg/kg, each other day) and irinotecan (50 mg/kg once at week) were delivered alone or in combination starting at day 5 from cell inoculation and for 24 days. TV was measured three times a week and data are represented as the mean ± SEM (N = 7). At day 21: *p < 0.005 for iVR1 and irinotecan compared to vehicle, §p < 0.0001 versus vehicle, #p < 0.005 vs iVR1 and irinotecan. (B), top, western blot analysis of VEGFR1 phosphorylation performed on mixed matching amounts of protein extracts belonging to the same experimental tumor group. Low, normalization with anti-VEGFR1 antibody performed on the same filter. The values of densitometry analyses are shown. Values (in percentages) were calculated as the ratio of degree of receptor phosphorylation with respect to the total receptor amounts. The value of 100 has been arbitrarily assigned to vehicle. (C), Kaplan-Meier survival curves of iVR1, irinorecan and bevacizumab (bevaciz, 5 mg/Kg two times a week) treatments, alone or in combination. Drugs were delivered as in A. Dashed line indicates 50% of survival. Bevaciz, irinotecan or iVR1 treatments were significantly lower compared to vehicle (p < 0.01) as well as the two combination treatments, iVR1 plus irinotecan and bevaciz plus irinotecan (p < 0.001).
Mentions: Among systemic treatments clinically approved for mCRC patients, irinotecan and bevacizumab containing regimens are largely used for their efficacy. Therefore, we evaluated if iVR1 activity might synergize with irinotecan, a camptotecin-based inhibitor of topoisomerase I [32]. Drugs were delivered starting at day 5 from cells inoculation and the combination treatment was compared to single treatments or vehicle (Figure 6A). At day 21 from cell inoculation, tumor growth inhibition induced by iVR1 was similar to that induced by irinotecan and both were significantly greater compared to vehicle (−58.3%, p < 0.005). Strikingly, the iVR1-irinotecan combination induced a very powerful inhibition of tumor growth already at day 21 (−82.1%, p < 0.0001 versus vehicle and −58.2%, p < 0.005, versus iVR1 and irinotecan alone), causing a progressive reduction of the tumors volume starting at day 16. Since we observed an almost total regression of tumors in the combination group, treatments were stopped seven days later. Indeed, at day 28, only two out of seven tumors were still detectable and for the next 20 days tumors were not measurable, with a delay in tumor relapse of about 50 days compared to vehicle-treated tumors. iVR1-treated tumors relapsed more rapidly than the irinotecan-treated ones, both reaching 1500 – 1600 mm3 average volume 20 and 30 days later, respectively, than vehicle-treated tumors (Figure 6A).

Bottom Line: Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein.Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection.Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.

View Article: PubMed Central - PubMed

Affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics "Adriano Buzzati-Traverso" - CNR, Naples, Italy.

ABSTRACT
To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.

No MeSH data available.


Related in: MedlinePlus