Abstract
BackgroundThe growth of solid tumors and their regrowth after treatment is dependent upon functional tumor vasculature. Some chemotherapeutic agents have shown anti-angiogenic properties but there are limited studies of the effect of chemotherapy on tumor vasculature. Here we investigate the effect of paclitaxel, 5-fluorouracil (5-FU) and doxorubicin on tumor vasculature in subcutaneous and orthotopic xenografts in mice.MethodsThe vascular density and percentage of functional blood vessels were evaluated in subcutaneous A431 human vulvar cancer xenografts, and in subcutaneous and orthotopic MCF-7 human breast cancer xenografts, following single doses of paclitaxel, 5-FU or doxorubicin.ResultsThere was no significant difference in total (CD31+) blood vessels between untreated ectopic and orthotopic MCF-7 tumors, but there was a significantly lower proportion of functional blood vessels in orthotopic tumors. After paclitaxel treatment, there was a decrease in functional tumor vasculature in A431 subcutaneous xenografts, followed by a subsequent rebound. There was a significant decrease in total vascular density on day 12 in A431 tumors following 5-FU or doxorubicin treatment, but no change in the percentage of functional vessels. An increase in functional blood vessels or percentage of functional vasculature was noted in MCF-7 subcutaneous and orthotopic xenografts following chemotherapy treatment.ConclusionsThere are differences in the vasculature and microenvironment of ectopic and orthotopic xenografts in mice. Anti-tumor effects of chemotherapy may be due, in part, to effects on tumor vasculature and may vary in different tumor models.
Highlights
The growth of solid tumors and their regrowth after treatment is dependent upon functional tumor vasculature
The present study aims to investigate whether the commonly used anticancer drugs paclitaxel, 5-FU, and doxorubicin modify the functional vasculature of subcutaneous A431 xenografts, and of subcutaneous or orthotopic MCF-7 xenografts
Effect of chemotherapy on tumor size in A431 and MCF-7 xenografts Mice were treated with a single dose of paclitaxel, doxorubicin, or 5-FU
Summary
The growth of solid tumors and their regrowth after treatment is dependent upon functional tumor vasculature. Some chemotherapeutic agents have shown anti-angiogenic properties but there are limited studies of the effect of chemotherapy on tumor vasculature. Adequate drug distribution within solid tumors is dependent on functional vasculature. Given the dependence of tumor growth on tumor vascularity, numerous studies have focused on targeting the process of angiogenesis. Drugs targeted against the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are being utilized in the clinic [4]. Data suggest that other anti-cancer agents, including chemotherapy and targeted agents such as EGFR inhibitors, might have effects to decrease the quantity or functionality of tumor vasculature [5,6,7,8,9,10]
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