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Evaluation of the "steal" phenomenon on the efficacy of hypoxia activated prodrug TH-302 in pancreatic cancer.

Bailey KM, Cornnell HH, Ibrahim-Hashim A, Wojtkowiak JW, Hart CP, Zhang X, Leos R, Martinez GV, Baker AF, Gillies RJ - PLoS ONE (2014)

Bottom Line: We show that MIA PaCa-2 tumors exhibit a "steal" effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction.The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining.Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America; Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida 33612, United States of America.

ABSTRACT
Pancreatic ductal adenocarcinomas are desmoplastic and hypoxic, both of which are associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are specifically activated in hypoxic environments to release cytotoxic or cytostatic effectors. TH-302 is a HAP that is currently being evaluated in a Phase III clinical trial in pancreatic cancer. Using animal models, we show that tumor hypoxia can be exacerbated using a vasodilator, hydralazine, improving TH-302 efficacy. Hydralazine reduces tumor blood flow through the "steal" phenomenon, in which atonal immature tumor vasculature fails to dilate in coordination with normal vasculature. We show that MIA PaCa-2 tumors exhibit a "steal" effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction. The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining. Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment. These studies support a combination mechanism of action for TH-302 with a vasodilator that transiently increases tumor hypoxia.

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MIA PaCa-2 tumors lack tonal mature vasculature.Hs766t, MIA PaCa-2 and SU.86.86 tumors were fixed and embedded in paraffin in preparation for IHC staining for tumor vasculature markers, CD31 and SMA. A) Representative images of tumors stained with CD31 and SMA. Scale bars represent 100 µm. Positive pixel analysis of B) CD31 and C) SMA staining across the whole area of a tumor. Data is presented as % Positivity [(Positive pixels/total pixels) × 100] ± SEM. * P<0.05; ** P<0.005.
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pone-0113586-g003: MIA PaCa-2 tumors lack tonal mature vasculature.Hs766t, MIA PaCa-2 and SU.86.86 tumors were fixed and embedded in paraffin in preparation for IHC staining for tumor vasculature markers, CD31 and SMA. A) Representative images of tumors stained with CD31 and SMA. Scale bars represent 100 µm. Positive pixel analysis of B) CD31 and C) SMA staining across the whole area of a tumor. Data is presented as % Positivity [(Positive pixels/total pixels) × 100] ± SEM. * P<0.05; ** P<0.005.

Mentions: Tumor samples from each cell line were analyzed histologically to characterize the vasculature. CD31 and smooth muscle actin (SMA) are two common tumor vasculature immunohistochemistry (IHC) markers that identify the presence (CD31), and the maturity and tone (SMA) of vasculature. Tumors with significant vasculature that are tonal would not be expected to exhibit the “steal” phenomenon, as the tumor vasculature would dilate in coordination with the systemic effects of hydralazine treatment. Using positive pixel analysis, we quantified the percentage of Hs766t, SU.86.86 and MIA PaCa-2 tumors that contained CD31 and SMA staining. Consistent with the prior results, SU.86.86 tumors had significantly more CD31 (p<0.05) staining than either Hs766t or MIA PaCa-2 (Fig. 3A–B), and significantly more SMA (p<0.005) than MIA PaCa-2 tumor samples (Fig. 3A, C). These data indicate that SU.86.86 tumors are well vascularized with mature vessels that would be expected to dilate in response to hydralazine treatment. MIA PaCa-2 and Hs766t tumors had similar amounts of CD31 staining (Fig. 3A–B). MIA PaCa-2 tumors had the least amount of SMA staining among the three tumors tested (Fig. 3A, C). These data indicate that MIA PaCa-2 vasculature is immature and atonal. As MIA PaCa-2 tumors displayed decreased tumor blood flow (Fig. 2) and a subsequent decrease in tumor pH (Fig. 1), we conclude that MIA PaCa-2 tumors exhibit the “steal” effect due to immature tumor vasculature.


Evaluation of the "steal" phenomenon on the efficacy of hypoxia activated prodrug TH-302 in pancreatic cancer.

Bailey KM, Cornnell HH, Ibrahim-Hashim A, Wojtkowiak JW, Hart CP, Zhang X, Leos R, Martinez GV, Baker AF, Gillies RJ - PLoS ONE (2014)

MIA PaCa-2 tumors lack tonal mature vasculature.Hs766t, MIA PaCa-2 and SU.86.86 tumors were fixed and embedded in paraffin in preparation for IHC staining for tumor vasculature markers, CD31 and SMA. A) Representative images of tumors stained with CD31 and SMA. Scale bars represent 100 µm. Positive pixel analysis of B) CD31 and C) SMA staining across the whole area of a tumor. Data is presented as % Positivity [(Positive pixels/total pixels) × 100] ± SEM. * P<0.05; ** P<0.005.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4273999&req=5

pone-0113586-g003: MIA PaCa-2 tumors lack tonal mature vasculature.Hs766t, MIA PaCa-2 and SU.86.86 tumors were fixed and embedded in paraffin in preparation for IHC staining for tumor vasculature markers, CD31 and SMA. A) Representative images of tumors stained with CD31 and SMA. Scale bars represent 100 µm. Positive pixel analysis of B) CD31 and C) SMA staining across the whole area of a tumor. Data is presented as % Positivity [(Positive pixels/total pixels) × 100] ± SEM. * P<0.05; ** P<0.005.
Mentions: Tumor samples from each cell line were analyzed histologically to characterize the vasculature. CD31 and smooth muscle actin (SMA) are two common tumor vasculature immunohistochemistry (IHC) markers that identify the presence (CD31), and the maturity and tone (SMA) of vasculature. Tumors with significant vasculature that are tonal would not be expected to exhibit the “steal” phenomenon, as the tumor vasculature would dilate in coordination with the systemic effects of hydralazine treatment. Using positive pixel analysis, we quantified the percentage of Hs766t, SU.86.86 and MIA PaCa-2 tumors that contained CD31 and SMA staining. Consistent with the prior results, SU.86.86 tumors had significantly more CD31 (p<0.05) staining than either Hs766t or MIA PaCa-2 (Fig. 3A–B), and significantly more SMA (p<0.005) than MIA PaCa-2 tumor samples (Fig. 3A, C). These data indicate that SU.86.86 tumors are well vascularized with mature vessels that would be expected to dilate in response to hydralazine treatment. MIA PaCa-2 and Hs766t tumors had similar amounts of CD31 staining (Fig. 3A–B). MIA PaCa-2 tumors had the least amount of SMA staining among the three tumors tested (Fig. 3A, C). These data indicate that MIA PaCa-2 vasculature is immature and atonal. As MIA PaCa-2 tumors displayed decreased tumor blood flow (Fig. 2) and a subsequent decrease in tumor pH (Fig. 1), we conclude that MIA PaCa-2 tumors exhibit the “steal” effect due to immature tumor vasculature.

Bottom Line: We show that MIA PaCa-2 tumors exhibit a "steal" effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction.The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining.Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States of America; Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida 33612, United States of America.

ABSTRACT
Pancreatic ductal adenocarcinomas are desmoplastic and hypoxic, both of which are associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are specifically activated in hypoxic environments to release cytotoxic or cytostatic effectors. TH-302 is a HAP that is currently being evaluated in a Phase III clinical trial in pancreatic cancer. Using animal models, we show that tumor hypoxia can be exacerbated using a vasodilator, hydralazine, improving TH-302 efficacy. Hydralazine reduces tumor blood flow through the "steal" phenomenon, in which atonal immature tumor vasculature fails to dilate in coordination with normal vasculature. We show that MIA PaCa-2 tumors exhibit a "steal" effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction. The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining. Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment. These studies support a combination mechanism of action for TH-302 with a vasodilator that transiently increases tumor hypoxia.

Show MeSH
Related in: MedlinePlus