Zusammenfassung
Four (1,3-diaminopropane)dichloroplatinum(II) complexes, linked to 5-hydroxy-2-(4-hydroxyphenyl)-3-methylindole by spacer groups of varying lengths, were synthesized and studied for their binding affinities for the calf uterine estrogen receptor. The RBA-values ranged from 1.0 to 4.4 (estradiol: RBA = 100). The endocrine activities of the complexes and their ligands, determined in the mouse ...
Zusammenfassung
Four (1,3-diaminopropane)dichloroplatinum(II) complexes, linked to 5-hydroxy-2-(4-hydroxyphenyl)-3-methylindole by spacer groups of varying lengths, were synthesized and studied for their binding affinities for the calf uterine estrogen receptor. The RBA-values ranged from 1.0 to 4.4 (estradiol: RBA = 100). The endocrine activities of the complexes and their ligands, determined in the mouse uterine weight test, are low. All compounds entered comparative tests using estrogen receptor-positive and negative mammary tumors models. The receptor levels in these tumors were determined by a modified h.p.l.c. micro assay. 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. At 10(-6) molar, the cell number was generally decreased by 50%. In vivo, the growth of estrogen receptor-positive MXT mouse tumors was strongly inhibited whereas the hormone-independent MXT mammary tumors showed only a minor response. The most active compound was the platinum complex with a xylidene spacer group (4d-PtCl2) showing a reduction of tumor weight of 84% after 6 weeks of treatment (3 x 20 mg/kg/week). One of the complexes (4c-PtCl2) and its ligand were tested for activity against the hormone sensitive DMBA-induced rat mammary carcinoma. The inhibitory effect of the complex was close to that of cisplatinum. In these experiments, no sign of toxicity was observed. The selective effect on estrogen receptor-positive tumors make an endocrine mode of action both for the complexes and their ligands likely.
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