Spheroids for studies of drug effects.

Abstract

A poorly vascularized solid tumour can have many properties that complicate the situation for drug treatment. The deficient blood vessel support will lead to regions consisting of well supported, proliferating cells, deeper-lying regions containing poorly supported, mainly resting cells, and regions distant from the vessels containing dead cells or massive necrosis. For example, this can lead to a suboptimal drug concentration in poorly vascularized regions of a tumour after IV injection, especially if the drug has a fast clearance from the plasma or if it has poor penetration properties into unvascularized tissue. Other factors influencing drug effects are differences in the micro-environment as a function of the distance from supporting blood vessels. Such micro-environmental factors might, for example, be cell-to-cell contacts and composition of the extracellular matrix, decreased oxygen tension due to poor support and high consumption of oxygen and decreased pH as a result of anaerobic glycolysis and accumulation of catabolic products. Proliferation gradients in the tumour nodules might give rise to additional variations in the drug effects. These variations will depend on the cell cycle specificity of the drug.