Preclinical toxicology and tissue platinum distribution of novel oral antitumour platinum complexes: ammine/amine platinum(IV) dicarboxylates

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.