[2001]-[XR9576]-[P-Glycoprotein Inhibitor][It had a high affinity for PGP]
BPC 2001 summary
PGP modulators could stop drug-resistant cancer
Intrinsic or acquired resistance to antineoplastic drugs leads to failure of chemotherapy but p-glycoprotein (PGP) inhibitors might overcome this problem, said Dr Prakash Mistry, research leader, Xenova Ltd.
Overproduction of PGP was a major cause of multidrug resistance in cancer cells. PGP was a membrane transporter whose natural role was to remove toxins from cells. However, it also effluxed a spectrum of hydrophobic and amphipathic drugs out of cells, including many important cytotoxic drugs (eg, vinca alkaloids and taxanes) and non-cytotoxic drugs (eg, verapamil and ciclosporin).
Other systems also caused multidrug resistance but their significance was not known.
PGP inhibitors or modulators appeared to inhibit PGP-mediated multidrug resistance. Dr Mistry said that they might be used first-line to reduce the frequency of emergent resistant cancer cell clones. However, research into this group of drugs had not been straightforward. A non-specific PGP inhibitor, PSC-833, had reached phase III clinical trials but its development had been stopped because of interactions seen with cytotoxic drugs and because it appeared to be ineffective.
Other similar drugs had also fallen by the wayside but specific PGP modulators were showing promise and had minimal interactions with cytotoxics.
Potentiating cell death
One such drug, the anthranilic acid derivative XR9576, had been shown to potentiate cytotoxic-mediated cell death when given with doxorubicin. XR9576 was a potent PGP modulator that had been shown to be active against a panel of mouse and human multidrug resistant cancer cell lines in vitro when given with a range of cytotoxics.
It had a high affinity for PGP and continued to block efflux of cytotoxic drugs for several hours after it had been removed from the cell incubating solution. XR9576 had a sufficiently long half-life in vivo to suggest that it could be given once daily and both its volume of distribution and bioavailability were high. In addition, it had no significant interactions with the important cytochrome p450 isoenzymes.
Phase I studies had shown that XR9576 was rapidly distributed and that doses of 1 and 2mg/kg completely inhibited PGP for at least 24 hours.
In an in vivo study, mice were given either paclitaxel or paclitaxel and XR9576. There was significant potentiation of the cytotoxic effect of paclitaxel in the mice that were given the drug with XR9576.
Phase II trials had looked for pharmacokinetic interactions with standard doses of paclitaxel, doxorubicin and vinorelbine, as well as safety and efficacy. No clinically significant interactions had been identified. Pivotal phase III trials in multidrug resistant cancers would start early next year, Dr Mistry said.
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