Anticancer drugs that enter cancer cells quickly may be less effective, that's according to work from Australian chemists. The University of Sydney team has demonstrated that rapid uptake of anticancer compounds by cells could limit how well they penetrate tumours. 

Using a spheroidal culture of cancer cells as a tumour model, Trevor Hambley and co-workers investigated the rate of cellular uptake and penetration of some model anticancer drugs. Their results suggest that competition between cell uptake and penetration deeper into a tumour means that drugs that rapidly enter cells near the surface are less able to penetrate deeper into and affect cells near the tumour centre. They found that one drug candidate with slower cellular uptake showed greater penetration into a cancer cell spheroid. In contrast, a model drug with a high cellular uptake rate rapidly entered cells near the spheroid surface, allowing much less of the drug to diffuse to, and then be taken up by, cells at the centre of the cancerous tissue. 

Slow cellular uptake of a platinum compound allows it to penetrate inside a model tumour rather than just accumulating at its edge

The researchers suggest that in the light of their results, the balance between cellular accumulation and tumour penetration may need to be shifted for some current anticancer agents. 'Rapid cellular uptake is usually considered highly desirable, but we have shown that slowing uptake can improve penetration which is also important,' says Hambley. Cells buried within tumours can have the most aggressive and drug resistant phenotypes, but as they are often not well supplied by blood vessels, it can be difficult for anticancer drugs to reach them. 'Poor penetration may be a major contributor to the failure of cancer chemotherapy,' Hambley says.

The work is welcomed by Sofi Elmroth, an expert in biochemistry, at Lund University, Sweden. She says that the research 'demonstrates in an elegant way that molecules with an improved tendency for cellular accumulation are typically less efficient when tissue permeability is measured. This observation highlights the need for tissue-like model systems in a relatively early phase of drug screening - and particularly so for anticancer active drug candidates - where efficient targeting of the central part of, for example, a tumour may well be the difference between an efficient cure and propagation of the disease.' 

Russell Johnson

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