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New Platinum, Titanium, and Ruthenium Complexes with Different Patterns of DNA Damage in Rat Ovarian Tumor Cells

Institute of Toxicology and Chemotherapy, German Cancer Research Center, 6900 Heidelberg, Federal Republic of Germany

DNA protein cross-links (DPC), DNA interstrand cross-links (ISCL), and DNA single strand breaks following treatment of experimental ovarian tumor cells (O-342) with five new metal complexes (three platinum, one titanium, one ruthenium compounds) were investigated at 6, 24, and 48 h after drug exposure and compared with their in vitro growth inhibitory potential. cis-Diamminedichloroplatinum(II) (cisplatin, DDP) served as reference drug. The following new compounds were tested: 18-crown-6-tetracarboxybis-diammineplatinum(II) (CTDP), cis-aminotrismethylenephosphonato-diammineplatinum(II) (AMDP), cis-diamminecyclohexano-aminotrismethylenephosphonato-platinum(II) (DAMP), diethoxybis-(1-phenylbutane-1,3-dionato)-titanium(IV) (budotitane), and trans-indazolium-tetrachlorobisindazole-ruthenate(III) (IndCR). At equimolar concentrations DNA cross-linking activity of the platinum agents decreased in the order cisplatin, CTDP, AMDP, DAMP; this was paralleled by growth inhibition in a cell proliferation assay. CTDP-induced interstrand cross-linking occurred more slowly compared to cisplatin (DDP) (6 h: CTDP, 73 ± 15 versus DDP, 365 ± 72 rad equivalents), but reached a peak similar to cisplatin 24 h after exposure (CTDP, 317 ± 68 versus DDP, 392 ± 116 rad equivalents). At this time point in contrast to DDP no DNA protein cross-links were observed for CTDP (total cross-links: CTDP 310 ± 71, DDP 1987 ± 436 rad equivalents). Thus, at 24 h, CTDP was found to be distinctly less reactive to proteins than DDP, and it is suggested that CTDP might be similar in its toxicity pattern to the structurally related compound carboplatin which was also reported to be less reactive to protein than DDP. By 48 h, CTDP- and DDP-induced interstrand cross-links were 65 ± 21 and 180 ± 33 rad equivalents, respectively. Although at a lower level, by 24 h, AMDP showed a ratio of ISCL to total cross-links (179 ± 39 versus 213 ± 31 rad equivalents), which was comparable to CTDP. The second biphosphonate complex DAMP was the least active platinum compound in terms of DNA damage, effecting only 16 ± 7 rad equivalents ISCL and 63 ± 28 rad equivalents total cross-links; similar to DDP, DAMP displayed a higher DPC fraction at 24 h. The titanium complex diethoxybis-(1-phenylbutane-1,3-dionato)-tita-nium(IV) showed dose-dependent inhibition of cell proliferation, while no significant DNA damage could be detected with the alkaline elution technique. These results, together with observations from other authors, indicating that space-filling planar aromatic ring systems are important for its antitumor activity, suggest as possible mechanism of action of diethoxybis-(1-phenylbutane-1,3-dionato)-titanium(IV) intercalation into the DNA. Following administration of the ruthenium compound IndCR only few ISCL and DPC were observed with a maximum at 6 h (ISCL, 15 ± 5; total cross-links, 49 ± 14 rad equivalents); thereafter both lesions were declining. Further studies on the mechanism of action of this class of antitumor agents should take into account that in hypoxic tumor tissue the Ru(III)-ion of IndCR might be reduced to Ru(II) which is known to be more reactive to DNA.

¹ To whom requests for reprints should be addressed.

Received 4/16/90. Accepted 3/21/91.