Margaretha Jennerwein

Influence of ring substituents on the antitumor effect of dichloro(1,2-diphenylethylenediamine)platinum(II) complexes

SummaryDiastereomeric para-substituted dichloro-(1,2-diphenylethylenediamine)platinum(II) complexes were synthesized and tested for their antitumor activity on the human MDA-MB 231 breast cancer cell line and the P 388 leukemia of the mouse. An interaction with the DNA was demonstrated by UV difference spectroscopy. The D,L configurated, 4-fluoro-substituted complex was the most active.

The tumor-inhibiting effect of isomeric dichloro(diphenylethylenediamine)platinum(II) complexes.

SummaryRing unsubstituted dichloro(diphenylethylenediamine)platinum(II) complexes show a dependence of their antitumor activity on the configuration and position of phenyl rings in ethylenediamine ligand. Dichloro(1,1-diphenylethylenediamine)platinum(II) (1d) and meso-dichloro(1,2-diphenylethylenediamine)-platinum(II) (meso-2d) have a weaker effect on the human breast-cancer cell line MDA-MB 231 and on rat leukemia L5222 than (±)-dichloro(1,2-diphenylethylenediamine)platinum(II) ((+)-2d) and its enantiomers (+)-2d and (-)-2d which cause marked and comparable inhibition of both tumors; (±)-2d is also active on ADJ/PC 6 plasmacytoma of the mouse and on cisplatin-, daunomycin-, and cisplatin/daunomycin-resistant Ehrlich ascites tumors of the mouse. The differences in activity of the diastereomers (±)-2d and meso-2d, for which distinct influences on the DNA secondary structure can be demonstrated CD spectroscopically may be explained by a steric hindrance of the drug-DNA interaction.

[dl-1,2-Bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II), a new compound for the therapy of ovarian cancer

SummaryThe synthesis of diastereoisomeric [1,2-bis (2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes,dl-3-PtCl2 andmeso-3-PtCl2, and their evaluation on the hormone-independent, human MDA-MB231 breast cancer cell line, on the cisplatin-sensitive and -resistant L1210 leukemia cell line, on the cisplatinresistant human NIH:OVCAR 3 ovarian cancer cell line, on the P-388 leukemia of the mouse and on the cisplatinsensitive and -resistant Ehrlich ascites tumor of the mouse are described. On all tumor modelsdl-3-PtCl2 produces a marked inhibitory effect. The diastereoisomermeso-3-PtCl2 is less active and more toxic. It is striking thatdl-3-PtCl2 leads to a pronounced inhibition of all cisplatin-resistant tumors. At non-toxic concentrationsdl-3-PtCl2 produces cytocidal effects on the NIH:OV-CAR 3 cell line. Thereforedl-3-PtCl2 is of interest for further evaluation for the therapy of ovarian cancer.

Tumor inhibiting [1,2-bis(fluorophenylethylenediamine]platinum-(II) complexes. Part I: synthesis

Abstract The synthesis of the diastereomeric 1,2-bis(2-,3- and 4-fluorophenyl)ethylenediamines 4–6, 10–12 from meso-1,2-bis(2-hydroxyphenyl)ethylenediamine and 2-, 3- and 4-fluorobenzaldehyde by a diaza-Cope-rearrangement and their conversion into the [1,2-bis(2-, 3- and 4-fluorophenyl)ethylenediamine]dihaloplatinum (II) complexes (Hal = Cl, 13–18; Hal = I, 19–24) with K2PtHal4 is described. From the diiodoplatinum(II) complexes (19–24) the better water soluble diaqua[1,2-bis(2-, 3- and 4-fluorophenyl)ethylenediamine]platinum(II) sulfates (25–30) and [1,2-bis(4-fluorophenyl)ethylenediamine]dinitratoplatinum (II) complexes (31 and 32) are obtained by reacting with Ag2SO4 or AgNO3. On the P388D1 leukemia cell line the racemic platinum (II) complexes are more active than their meso-analogues and equiactive with cis-platin. The position of the fluorine atom and the kind of the leaving group do not influence the activity.

The role of DNA repair in resistance of L1210 cells to isomeric 1,2-diaminocyclohexaneplatinum complexes and ultraviolet irradiation

Resistance to cisplatin in several murine leukemia L1210 cell lines is due to enhanced DNA repair. Other platinum complexes, particularly those containing 1,2-diaminocyclohexane (DACH) are of interest as they effectively kill both sensitive (L1210/0) and cisplatin-resistant (L1210/DDP) cell lines. An L1210/DACH cell line has been developed that is preferentially resistant to DACH-Pt complexes. In the current experiments, we investigated the role that DNA repair has in resistance to DACH-Pt compounds. The DACH ligand exists in 3 isomeric forms which exhibit markedly different activities in the various resistant cell lines. Generally, R,R-DACH-Pt was the most effective isomer. DNA repair was assayed by host-cell reactivation of platinated pRSVcat. DNA damage induced by all the isomeric DACH-Pt-SO4 complexes markedly reduced CAT expression in sensitive L1210/0 cells. One adduct per transcribed strand of the cat gene inhibited CAT expression demonstrating that the sensitive cells exhibited no detectable DNA repair. All the resistant cell lines reactivated the plasmid DNA whether damaged with cisplatin or any of the 3 DACH-Pt isomers. Therefore, resistance to both cisplatin and DACH-Pt appears to be mediated by enhanced DNA repair, but the level of reactivation of the transfected plasmid did not correlate with the toxicity of each analogue. These results suggest that some additional event(s) is responsible for the substrate specificity of repair of genomic DNA. These resistant cell lines also exhibited resistance to UV irradiation but this was much less than, and did not correlate with the degree of resistance to either cisplatin or DACH-Pt. However, there was a good correlation between resistance to UV irradiation and reactivation of UV-damaged plasmid DNA. This enhanced reactivation suggests that enhanced repair may be the sole reason for the resistance to UV irradiation.

Development of selectively acting platinum complexes

The antitumor activity of the stereoisomers of dichloro-1,2-bis(4-hydroxyphenyl)ethylenediamineplatinum (I) was studied in vitro (on ADJ/PC6 plasmacytoma and MDA breast cancer cells) as well as in vivo (in mice bearing ADJ/PC6 plasmacytoma). Whereas (-)-I [91326-62-4] was highly active both in vivo and in vitro, the other isomers were less active; the meso isomer [91265-66-6] was more or less inactive. The 1,2-bis(4-hydroxyphenyl)ethylenediamine moiety renders these Pt complexes more selective for estrogen receptors. The antitumor activity of the (-)-isomer was not affected by diethylstilbestrol, indicating that the antitumor action of the Pt complexes is mainly due to their cytotoxic effects.