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[1, 2‐Bis(2, 6‐difluoro‐3‐hydroxyphenyl)ethylene‐diamine]platinum(II) Complexes, Compounds for the Endocrine Therapy of Breast Cancer ‐ Mode of Action II: Contribution of Drug Inactivation, Cellular Drug Uptake and Sterical Factors in the Drug‐Target Interaction to the Antitumor Activity
Author(s) -
Schertl Sabine,
Hartmann Rolf W.,
BatzlHartmann Christine,
Bernhardt Günther,
Spruß Thilo,
Beckenlehner Karin,
Koch Marion,
Krauser Rudolf,
Schlemmer Richard,
Gust Ronald,
Schönenberger Helmut
Publication year - 2004
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200300856
Subject(s) - chemistry , cisplatin , cytotoxicity , ethylenediamine , in vivo , mechanism of action , cancer cell , breast cancer , in vitro , stereochemistry , cancer , programmed cell death , biochemistry , cancer research , pharmacology , apoptosis , medicine , biology , chemotherapy , organic chemistry , microbiology and biotechnology
Abstract The marked activity of [meso‐1, 2‐bis(2, 6‐difluoro‐3‐hydroxyphenyl)ethylenediamine]platinum(II) (meso‐3‐PtLL′, L, L′ = Cl 2 or L = OH 2 , L′ = OSO 3 ) on the hormone‐sensitive MXT‐M‐3, 2 breast cancer implanted in mice is most probably due to a mechanism based on the reduction of the endogenous estrogen level. Cytotoxic effects which are poorly pronounced in experiments on several breast cancer cell lines (e.g. MCF‐7), do not significantly contribute to the anti‐breast cancer activity of this compound. In contrast to this, the standard cisplatin and the structurally related comparison compound [meso‐1, 2‐bis(4‐fluorophenyl)ethylenediamine]platinum(II) (meso‐4‐PtLL′, L, L′ = Cl 2 or L = OH 2 , L′ = OSO 3 ) are strongly active in vivo as well as in vitro . Both effects entail programmed cell death, which is responsible for the inhibition of the tumor growth. The minor cytotoxicity of meso‐3‐PtLL′ in breast cancer cell cultures is caused neither by an inappropriate rate of reaction with bionucleophiles (e.g. by a too fast inactivation by plasma proteins) nor solely by the observed poor absorption by the tumor cells resulting in an insufficient drug concentration at the DNA. Additionally, an impeded reaction with biologically important, guanine‐rich sequences of DNA (owing to the 2, 6‐standing F atoms which hinder the drug‐target inter action) must be assumed as cause of its marginal cytotoxicity.