Abstract
BackgroundAnti-cancer drugs access solid tumors via blood vessels, and must penetrate tumor tissue to reach all cancer cells. Previous studies have demonstrated steep gradients of decreasing doxorubicin fluorescence with increasing distance from blood vessels, such that many tumor cells are not exposed to drug. Studies using multilayered cell cultures show that increased P-glycoprotein (PgP) is associated with better penetration of doxorubicin, while PgP inhibitors decrease drug penetration in tumor tissue. Here we evaluate the effect of PgP expression on doxorubicin distribution in vivo.MethodsMice bearing tumor sublines with either high or low expression of PgP were treated with doxorubicin, with or without pre-treatment with the PgP inhibitors verapamil or PSC 833. The distribution of doxorubicin in relation to tumor blood vessels was quantified using immunofluorescence.ResultsOur results indicate greater uptake of doxorubicin by cells near blood vessels in wild type as compared to PgP-overexpressing tumors, and pre-treatment with verapamil or PSC 833 increased uptake in PgP-overexpressing tumors. However, there were steeper gradients of decreasing doxorubicin fluorescence in wild-type tumors compared to PgP overexpressing tumors, and treatment of PgP overexpressing tumors with PgP inhibitors led to steeper gradients and greater heterogeneity in the distribution of doxorubicin.ConclusionPgP inhibitors increase uptake of doxorubicin in cells close to blood vessels, have little effect on drug uptake into cells at intermediate distances, and might have a paradoxical effect to decrease doxorubicin uptake into distal cells. This effect probably contributes to the limited success of PgP inhibitors in clinical trials.
Highlights
Anti-cancer drugs access solid tumors via blood vessels, and must penetrate tumor tissue to reach all cancer cells
Repopulation of surviving tumor cells between courses of chemotherapy is an important mechanism of drug resistance [24,25,26,27,28], and viable cells distal from blood vessels that do not receive cytotoxic concentrations of drug might be an important source of such repopulation [29]
In well-vascularized areas drug distribution is relatively uniform; Similar to data for multilayered cell cultures (MCC), our results show an increase in doxorubicin distribution in the PgP overexpressing tumors AR1 and MCF-7/ADR compared to their wild-type variants EMT6 and MCF-7, respectively
Summary
Anti-cancer drugs access solid tumors via blood vessels, and must penetrate tumor tissue to reach all cancer cells. Previous studies have demonstrated steep gradients of decreasing doxorubicin fluorescence with increasing distance from blood vessels, such that many tumor cells are not exposed to drug. In particular there are steep gradients of decreasing doxorubicin fluorescence with increasing distance from blood vessels in tumors grown in mice and in human breast cancer, suggesting that limited drug penetration may be an important cause of resistance to treatment [6,7]. Many of the anticancer drugs in clinical use are natural products, or derivatives of natural products (e.g. anthracyclines such as doxorubicin, vinca alkaloids such as vincristine and taxanes) and they share common mechanisms of resistance Many of these drugs are high affinity substrates for energy-dependent membrane transporter proteins that act to pump drugs out of cells. Other factors may contribute in explaining the limited effectiveness of PgP inhibitors in vivo
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