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Notes: Summary Although the antitumour agent flavone-8-acetic acid (FAA) exhibits remarkable activity against murine solid tumours, its clinical use has a number of pharmacological drawbacks, including low dose potency and dose-dependent pharmacokinetics. Xanthenone-4-acetic acid (XAA) and its 5,6-dimethyl derivative (5,6-MeXAA) were synthesised during a search for better analogues of FAA. The maximal tolerated doses (MTDs) of 5,6-MeXAA, XAA and FAA in BDF1 mice were 99, 1,090 and 1,300 μmol/kg, respectively. At the MTD, 5,6-MeXAA displayed the following pharmacokinetic properties: maximal plasma concentration, 600 μM; mean residence time, 4.9 h; AUC, 2,400 μmol h l−1; and volume of steady-state distribution, 0.2 l/kg. All compounds displayed nonlinear elimination kinetics at the MTD, but when the logarithm of the AUC was plotted against that of the delivered dose, the slope of the regression line for 5,6-MeXAA was found to be 1.2 as opposed to 1.4 for XAA and 1.98 for FAA. 5,6-MeXAA thus showed only a slight deviation from dose-independent kinetics. 5,6-MeXAA bound to plasma proteins in a manner similar to that exhibited by FAA, although the plasma concentration of free drug was lower for the former than for the latter. As a consequence, the calculated maximal free drug concentration for 5,6-MeXAA in plasma was 23 times lower than that for FAA.

Notes: Abstract The preclinical toxicology and tissue platinum distribution of a series of six orally given antitumour platinum complexes [ammine/amine platinum(IV) dicarboxylates] with structural variations of their alicyclic amine (c-C5, c-C6 or c-C7), axial dicarboxylate (CH3, C3H7 or NHC2H5) or leaving substituents (Cl2 or OCOOCO) was studied in the mouse. Platinum tissue levels measured at 48 h after a single oral dose at 0.5 of the MTD were highest in the liver (6.0–19 μm/g) and second highest in the kidney (2.8–12 μg/g), and these levels were up to 5 times higher than those reported with equi-toxic doses of i.v. cisplatin and i.v. carboplatin. Platinum levels in the lung, heart, spleen, skin, skeletal muscle and brain were all〈-3.1 μg/g at this dose level. Liver platinum levels measured at 2 h, 2 days, 6 days and 10 days after a single oral dose at the MTD ranged widely (from 15 to 109 μg platinum/g), were related to the number of carbon atoms in the axial dicarboxylate and alicyclic amine groups (r=0.9389) and showed a diversity of time-course profiles. Elevations of plasma ALT activity were recorded with single oral doses of JM225 and JM256 at the MTD. Accumulation of platinum in the liver with repeated oral dosing weekly for 4 consecutive weeks at 0.5 of the MTD occurred with JM269 (3.3-fold increase,P〈0.05) and JM 225 (2.4-fold increase,P〈0.05), and elevated plasma ALT activity (44±33 IU/I) was recorded with repeated oral doses of JM269. JM216 was selected from this series of analogues for further study on the basis of the elevated plasma ALT activity (JM225, JM256 and JM269), liver platinum accumulation (JM269 and JM225), poor activity against human ovarian carcinoma xenografts (JM291) or severe emetogenesis (JM221) of other examples. Following a single oral dose of JM216 at the MTD, transient reductions in the WBC (nadir, 1.6×109/ 1,2 days, 74% reduction), platelet count (nadir, 613×109/l, 10 days, 33% reduction) and bone marrow cellularity (nadir, 0.5×107 nucleated cells/femur, 4 days, 75% reduction) were found, and these had recovered by 21 days after treatment. Jejunal mucosal disaccharidase activity following single MTDs indicated that small-intestinal mucosal damage was less severe for oral JM216 (nadir maltase activity, 68%±16% of control, NS) than for i.v. cisplatin (nadir maltase activity, 35%±6.0% of control,P〈0.01) and i.v. carboplatin (nadir maltase activity, 38%±6.4% of control,P〈0.01). In conclusion, the liver is the major tissue platinum deport for orally delivered ammine/amine platinum(IV) dicarboxylates and is a site of toxicity for examples of this class. Oral JM216 causes dose-limiting leucopenia but produces less gastrointestinal toxicity than either i.v. cisplatin or i.v. carboplatin at the MTD in the mouse.

Notes: Abstract. The preclinical toxicology and tissue platinum distribution of a series of six orally given antitumour platinum complexes [ammine/amine platinum(IV) dicarboxylates] with structural variations of their alicyclic amine (c-C5, c-C6 or c-C7), axial dicarboxylate (CH3, C3H7 or NHC2H5) or leaving substituents (Cl2 or OCOOCO) was studied in the mouse. Platinum tissue levels measured at 48 h after a single oral dose at 0.5 of the MTD were highest in the liver (6.0 – 19 μg/g) and second highest in the kidney (2.8 – 12 μg/g), and these levels were up to 5 times higher than those reported with equi-toxic doses of i. v. cisplatin and i. v. carboplatin. Platinum levels in the lung, heart, spleen, skin, skeletal muscle and brain were all ≤3.1 μg/g at this dose level. Liver platinum levels measured at 2 h, 2 days, 6 days and 10 days after a single oral dose at the MTD ranged widely (from 15 to 109 μg platinum/g), were related to the number of carbon atoms in the axial dicarboxylate and alicyclic amine groups (r = 0.9389) and showed a diversity of time-course profiles. Elevations of plasma ALT activity were recorded with single oral doses of JM225 and JM256 at the MTD. Accumulation of platinum in the liver with repeated oral dosing weekly for 4 consecutive weeks at 0.5 of the MTD occurred with JM269 (3.3-fold increase, P 〈0.05) and JM225 (2.4-fold increase, P 〈0.05), and elevated plasma ALT activity (44±33 IU/l) was recorded with repeated oral doses of JM269. JM216 was selected from this series of analogues for further study on the basis of the elevated plasma ALT activity (JM225, JM256 and JM269), liver platinum accumulation (JM269 and JM225), poor activity against human ovarian carcinoma xenografts (JM291) or severe emetogenesis (JM221) of other examples. Following a single oral dose of JM216 at the MTD, transient reductions in the WBC (nadir, 1.6×109/l, 2 days, 74% reduction), platelet count (nadir, 613×109/l, 10 days, 33% reduction) and bone marrow cellularity (nadir, 0.5×107 nucleated cells/femur, 4 days, 75% reduction) were found, and these had recovered by 21 days after treatment. Jejunal mucosal disaccharidase activity following single MTDs indicated that small-intestinal mucosal damage was less severe for oral JM216 (nadir maltase activity, 68%±16% of control, NS) than for i. v. cisplatin (nadir maltase activity, 35%±6.0% of control, P 〈0.01) and i. v. carboplatin (nadir maltase activity, 38%±6.4% of control, P 〈0.01). In conclusion, the liver is the major tissue platinum depot for orally delivered ammine/amine platinum(IV) dicarboxylates and is a site of toxicity for examples of this class. Oral JM216 causes dose-limiting leucopenia but produces less gastrointestinal toxicity than either i. v. cisplatin or i. v. carboplatin at the MTD in the mouse.

Notes: Summary Treatment of C57Bl/6×DBA/2 mice with the maximal tolerated dose of flavone-8-acetic acid (FAA, 1300 μmol/kg), xanthenone-4-acetic acid (XAA, 1090 μmol/kg), or its dose-potent derivative 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA, 100 μmol/kg) resulted within 24 h in a dramatic reduction in the number of circulating lymphocytes, an elevation in haemoglobin concentrations and a reduction in platelet numbers. Neutrophil counts either remained unchanged or were slightly elevated. All three compounds caused a marked loss of cells in the thymus. Examination of histological sections of thymus at 48 h following treatment with XAA revealed a selective depletion of cortical thymocytes and no effects on the epithelium or other thymic structures. A transient decrease in cell numbers was seen in the spleen and femoral bone marrow, with recovery to normal levels occurring within 3 days. The number of haemopoietic stem cells, colony-forming units in culture (CFU-c), in the femoral bone marrow increased after drug administration despite the occurrence of a decrease in the overal number of cells in the femur. In contrast to the increase in CFU-c numbers seen in vivo, 2 h exposure of bone-marrow cells to FAA, XAA or 5,6-MeXAA in vitro resulted in a decrease in the surviving fraction of CFU-c. The results are consistent with the hypothesis that the in vivo haematological effects of these compounds are indirect, perhaps being mediated through the induction of cytokines, and contrast with the haematological effects of conventional antitumour agents. The biochemical and haematological effects are unlikely to be the cause of the acute toxicity observed for these compounds.