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A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the(More)
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of(More)
There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available three-dimensional techniques are(More)
The plasma, urinary and biliary clearances of cisplatin and its non-nephrotoxic analogue, Carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II, CBDCA, JM8) have been determined in mice and rats following intravenous administration of the compounds. The plasma concentration-time curves were biphasic during the time period studied (0-60 min),(More)
This study compared the effect on sensory nerve conduction velocity in the hind limb of chronically treated age-matched rats of a novel lipophilic p.o. platinum complex [bisacetatoamminedichlorocyclohexylamine-platinum(IV)], with that of neurotoxic platinum complexes cisplatin and tetraplatin. Tetraplatin (i.p.) first caused slowing of sensory nerve(More)
In rats a maximal tolerated dose of carboplatin (60 mg kg-1, i.v.) caused severe anaemia, leucopenia and thrombocytopenia. These indices of haematological toxicity were also observed with a maximal tolerated dose of cis-platin (6.5 mg kg-1, i.v.), but reductions in blood cell counts were less than those observed with carboplatin. Anaemia was deduced to be(More)
The expression of the BCL-2 family proteins, BCL-2, BAX, BCL(XL) and BAK have been determined in a panel of 12 human ovarian carcinoma cell lines encompassing a wide range in sensitivity to cisplatin. Whereas BAX, BCL(XL) and BAK levels did not correlate with sensitivity, there was a statistically significant inverse correlation (r = -0.81; P = 0.002)(More)
A novel sterically hindered platinum complex, AMD473 [cis-amminedichloro(2-methylpyridine) platinum(II)], designed primarily to be less susceptible to inactivation by thiols, has shown in vitro activity against several ovarian carcinoma cell lines. Notably, AMD473 has shown activity in vitro in human carcinoma cells that have acquired cisplatin resistance(More)
Four models of acquired resistance to the clinically-used platinum drug, oxaliplatin, have been established using human tumour cell lines in vitro; two colon (HCT116 and HT29) and two ovarian (A2780 and CH1). Levels of acquired resistance ranged from 3.0- to 15.8-fold with levels of resistance higher in the colon relative to the ovarian carcinoma cell(More)
ZD0473 is a new generation hindered platinum agent currently undergoing worldwide Phase II clinical studies. The in vitro cytotoxicity of ZD0473 either alone or in combination with the anticancer drugs paclitaxel, gemcitabine, vinorelbine, topotecan and doxorubicin was determined using four human ovarian carcinoma cell lines and by the sulphorhodamine B(More)