thiourea and Leukemia-P388

To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH(3) by an iminoether group, trans-[PtCl(2)(Z-HN=C(OMe)Me)(NH(3)] and trans-[PtCl(2)(E-HN=C(OMe)Me)(NH(3)] complexes (differing in the Z or E configuration of iminoether, and abbreviated mixed Z and mixed E, respectively), have been synthesized. In a panel of human tumor cell lines, both mixed Z and mixed E show a cytotoxic potency higher than that of transplatin, the mean IC(50) values being 103, 37, and 215 microM, respectively. In vivo mixed Z is more active and less toxic than mixed E in murine P388 leukemia and retains its efficacy against SK-OV-3 human cancer cell xenograft in nude mice. In the reaction with naked DNA, mixed Z forms monofunctional adducts that do not evolve into intrastrand cross-links but close slowly into interstrand cross-links between complementary guanine and cytosine residues. The monofunctional mixed Z adducts are removed by thiourea and glutathione. The interstrand cross-links behave as hinge joints, increasing the flexibility of DNA double helix. The mixed Z, transplatin, and cisplatin interstrand cross-links, as well as mixed Z monofunctional adducts are not specifically recognized by HMG1 protein, which was confirmed to be able to specifically recognize cisplatin d(GpG) intrastrand cross-links. These data demonstrate that the DNA interaction properties of the antitumor-active mixed Z are very similar to those of transplatin, thus suggesting that clinical inactivity of transplatin could not depend upon its peculiar DNA binding mode.

Topics: Animals; Antineoplastic Agents; Cisplatin; Cross-Linking Reagents; Disease Models, Animal; DNA; DNA Adducts; DNA Footprinting; DNA Restriction Enzymes; DNA-Directed RNA Polymerases; Drug Screening Assays, Antitumor; High Mobility Group Proteins; Humans; Leukemia P388; Mice; Nucleic Acid Conformation; Oligonucleotides; Rats; Thiourea; Tumor Cells, Cultured

Two novel series of thio compounds bearing internal structural modifications of hexestrol were synthesized as potential anticancer agents. The first contains several N-substituted thiourea functions, and the second contains various N4-substituted-3-thiosemicarbazide moieties in place of one alpha-ethyl group of hexestrol dimethyl ether. The products showed no antileukemic activity in the P-388 lymphocytic leukemia system and did not exhibit any anticonvulsant or estrogenic properties.

Topics: Animals; Antineoplastic Agents; Hexestrol; Leukemia P388; Mice; Semicarbazides; Structure-Activity Relationship; Thiourea