Lymphoid suppression by cis-platinum(II) amines. What are the active agents?

Cisplatin and its various hydrolysis products were tested in vitro for their effects on the incorporation of [3H]thymidine into lymphocytes isolated from thymuses, spleens and stimulated lymph nodes of rats. Neither cisplatin nor the mu-hydroxo-bridged oligomers formed after hydrolysis significantly inhibited thymidine incorporation at pH 7.4. However, freshly neutralised cis-diaquodiammineplatinum(II) was a potent inhibitor of thymidine incorporation by all three lymphocyte populations. In other experiments, rats were given either cisplatin or one of its hydrolysis products i.p. Cells isolated 17 hr later from the thymuses of all of these animals incorporated much less [3H]thymidine into DNA in vitro than thymocytes from saline-injected control animals. None of the platinum species significantly affected either [3H]uridine incorporation or the oxidation of [14C]octanoate to 14CO2 by the thymocytes. Evidence for anation of di- and tri-nuclear mu-hydroxo-bridged platinum(II)amines by chloride has been obtained from spectrophotometric analyses and 195Pt-NMR studies. Thiols also reacted with these platinum complexes at different rates (cis-[(NH3)2Pt(H2O)2]2+ much greater than derived oligomers greater than cisplatin). Various mechanisms for lymphoid suppression by cisplatin and its hydrolysis products are considered. It is proposed that cisplatin and its mu-hydroxo-bridged derivatives owe their lymphotoxic activity primarily to their in vivo transformation to platinum species containing aquo ligands.