In vitro and in vivo characterization of XR11576, a novel, orally active, dual inhibitor of topoisomerase I and II.

XR11576, a novel phenazine, was developed as an inhibitor of both topoisomerase I and II. This study characterized the ability of XR11576 to inhibit both enzymes, and determined its in vitro and in vivo antitumor efficacy against a number of murine and human tumor models. XR11576 was a potent inhibitor of purified topoisomerase I and IIalpha, and exhibited similar potency for both enzymes.

Studies on quinazolinones as dual inhibitors of Pgp and MRP1 in multidrug resistance.

The syntheses and SAR studies of various quinazolinone compounds are described for the dual inhibition of Pgp and MRP1 in multidrug resistance.

Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents.

Heterocyclic phenazinecarboxamides were prepared by condensation of aminoheterocycles and 2-halo-3-nitrobenzoic acids, followed by reductive ring closure and amidation. They showed similar inhibition of paired cell lines that underexpressed topo II or overexpressed P-glycoprotein, indicating a non topo II mechanism of cytotoxicity and indifference to P-glycoprotein mediated multidrug resistance. Compounds with a fused five-membered heterocyclic ring were generally less potent than the pyrido[4,3-a]phenazines.

Novel angular benzophenazines: dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents.

A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein.

Antitumor activity of XR5944, a novel and potent topoisomerase poison.

Inhibitors of topoisomerases are widely used in the treatment of cancer, including inhibitors of topoisomerase I (camptothecin analogs such as irinotecan and topotecan) and topoisomerase II (etoposide and doxorubicin). The novel bis-phenazine, XR5944, is a joint inhibitor of topoisomerase I and II as shown by the stabilization of topoisomerase-dependent cleavable complexes. XR5944 demonstrated exceptional activity against human and murine tumor cells in vitro and in vivo.

In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576.

The overexpression of P-glycoprotein (P-gp) on the surface of tumor cells causes multidrug resistance (MDR). This protein acts as an energy-dependent drug efflux pump reducing the intracellular concentration of structurally unrelated drugs. Modulators of P-gp function can restore the sensitivity of MDR cells to such drugs.

Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives.

We have synthesised and evaluated a series of anthranilamide based modulators of P-glycoprotein. These studies have identified XR9576(2), a potent inhibitor of P-glycoprotein in vitro and in vivo. The general synthesis and the SAR of these compounds are described.

Serum lipoproteins and atherosclerosis in animals.

The lipoproteins have been examined in more than 300 serum or plasma samples taken during life or at post mortem from a fairly wide range of mammals, birds and reptiles. The material, which was collected over a period of several years, was subjected to a limited range of lipid analyses, but all specimens were submitted to electrophoresis with paper or cellulose acetate membrane as supporting medium. The lipoprotein pattern in mammals appears to be basically similar to that in man, but there are wide variations in lipid concentrations; the highest levels being found in bears, seals and primates.

The investigation of lipoproteins in lymph and other body fluids by paper electrophoresis.

The protein and lipid electrophoresis patterns of lymph and various body fluids have been examined. Chylous fluids produce a characteristic lipid pattern with a dense deposit at the origin and a lipid trail. The value of centrifuging turbid fluids at high speed before electrophoresis is stressed.