title: 2-Phenylindole-linked [2-(aminoalkyl)pyridine]dichloroplatinum(II): complexes with a selective action on estrogen receptor positive mammary tumors.
abstract: A number of [2-(aminomethyl)pyridine]dichloroplatinum(II) complexes, linked to 5-hydroxy-2-(4-hydroxyphenyl)indoles by alkyl spacer groups of varying lengths, were synthesized and studied for their binding affinities for the calf uterine estrogen receptor. Their relative binding affinity (RBA) values ranged from 1.0 to 5.2% (estradiol, RBA = 100%). Highest affinities were found with complexes possessing a (CH2)5- or (CH2)6-bridge between the pyridine aminomethyl group and the indole nitrogen. Endocrine activities of the complexes and their ligands, determined in the mouse uterine weight test, were low. All compounds entered comparative tests using estrogen receptor positive and negative mammary tumor models. In cell culture, a growth inhibiting effect was only observed in hormone-sensitive MCF-7 cells, but not in hormone-independent MDA-MB 231 cells. In this assay, there was no significant difference between complexes and their ligands. In vivo, the growth of estrogen receptor positive MXT mouse mammary tumors was strongly inhibited by the complexes whereas the hormone-independent MXT mammary tumors showed only a minor response. At a dose of 3 X 20 mg/kg per week, complexes 10d-g reduced the tumor weight by ca. 80% after 6 weeks of treatment. This effect was generally stronger than that exerted by the ligands. The doses applied were well tolerated. Since the complexes described in this paper require the estrogen receptor for their action, a mechanism similar to that of antiestrogens is assumed.
authors.affiliation: Institut für Pharmazie, Universität Regensburg, Federal Republic of Germany.
authors.forename: N G
authors.initials: NG
authors.lastname: Knebel
authors.forename: E
authors.initials: E
authors.lastname: von Angerer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011960:Receptors, Estrogen