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The tumour microenvironment : mapping the microregional effects of drugs Huxham, Lynsey Anne

Abstract

Rapid cell proliferation combined with a lack of adequate vascular supply can result in cells far from vasculature becoming oxygen and nutrient deprived. These hypoxic and quiescent cells can be resistant to radio- and chemotherapies and their location can result in sub-therapeutic exposures to drug. Insight into extra-vascular drug distribution and microenvironment changes in tumours could improve drug scheduling and delivery, as well as aid in the screening and rational design of new anti-cancer drugs. The main objective of this research is to examine the tumour microenvironment after drug administration to determine which drugs penetrate effectively and to observe changes in vasculature, proliferation, and hypoxia. This is achieved by staining and imaging various markers in tumour cryosection and examining their locations relative to each other. For example, the fraction of dividing cells as a function of distance from vasculature can be used to evaluate the extent of drug effect. As well, analysis of the microenvironmental differences between tumours, after treatment, can provide insight into which characteristics lead to effective tumour control. From examining the effects of pyrimidine analogues on proliferation in relation to vasculature we were able to show a differential effect on cells far from vasculature compared to cells proximal to vasculature. Additionally, we have shown the hypoxic cytotoxin tirapazamine unexpectedly caused central vascular dysfunction. This was characterized by a cessation of vascular perfusion in the central area of treated tumours, which became necrotic over time. By using similar tumour mapping techniques we were then able to show that increasing the vascular oxygen level, by carbogen breathing, does not completely eradicate the vascular targeting effect of tirapazamine. We further suggest the inhibition of NOS, by tirapazamine, may lead to vessel constriction and thus increased hypoxia subsequently causing greater activation of tirapazamine. During this research it became clear the response of proliferating tumour cells to drug is not necessarily uniform and additionally that drugs may exert unexpected mechanisms of action. The observations made by mapping the tumour microenvironment can be easily missed using traditional in vitro cell monolayer experiments or growth delay and clonogenic assays.

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