Trans-DPP

Fig. 17 Structure of the anionic porphyrin cis- and trans-DPPS and of the A— and A— enantiomers of [Ru(phen)3]2+. Modified from [50, 51]...

Fig. 20 (a) Absorption spectrum of a 5 pM trans-DPPS aqueous solution, (b) Absorption spectra of a 5 pM A-Ru[(Phen)3]2+ aqueous solution (solid line) in the absence and in the presence of different concentrations of cw-DPPS. (c) CD spectra of a 5 pM A-Ru[(Phen)3]2+ solution (solid line) in the absence and in the presence of different concentrations of cw-DPPS. (d) RLS spectra of a 5 pM A-Ru[(Phen)3]2+ solution [solid line) in the absence and in the presence of different concentrations of cw-DPPS. The RLS spectrum of a 5 pM cw-DPPS aqueous solution (dotted line) is also reported. Modified from [50]... 

Fig. 21 Emission spectrum of a 5 pM A-Ru[(Phen)3]2+ aqueous solution in the absence (curve a, lex = 262 nm) and in the presence of 5 pM trans-DPPS (curve c). Curve b is the emission spectrum of a 5 pM trans-DPPS aqueous solution (lex = 262 nm). Modified from [50]...

DPPS or trans-DPPS (not removable) added chirality in porphyrin aggregate)... 

In carcinogenesis studies in vivo, cis-DDP produced lung adenomas in A/Jax mice, skin papillomas in CDl mice when administered in combination with croton oil, and sarcomas at the site of injection in F344 rats (13). When administered at maximally tolerated doses, trans-DPP did not induce tumours in the lung adenoma or skin papilloma systems, as expected from its low mutagenicity (14). 

By blocking the various possible binding sites in the purine bases by either methylation or protonation, Mansy et al. (22) defined the sites most likely to be involved in reaction with either cis or trans-DPP > They concluded that the cis isomer forms a bidentate chelate with either the 6-NH2 and N-7, or the... 

The relative toxicities of the cis and trans isomers of the platinum(II) neutral complexes, can be defined by the slopes of the survival curves (Dq) obtained by treating Hela cells in culture. Comparison of these two sets of values indicated that the relative abilities of cis and trans-DPP compounds to crosslink DNA in vivo (but not in vitro) were related to their cytotoxic action ( 9,3 ). These studies therefore suggest that interstrand crosslinking with both the platinum(II) compounds, but not necessarily platinum(IV) compounds, may be important in inducing their cytotoxic effects and that the cis isomer is most effective in inducing the reaction. 

Johnson et al. (66) used an in vitro T7 DNA replication system which copies exogenous T7 DNA by a mechanism that closely mimics in vivo DNA replication to demonstrate the relative inhibitory effect of either pyrimidine dimers or bound 195mpt-labelled cis or trans-DPP. It could be shown that cis-DDP and pyrimidine dimers inhibited DNA replication to the same extent per lesion (63% inhibition per 3 x 10 lesions/nucleotide phosphate) and the trans-DPP was 5-fold less inhibitory. 

The ISC produced by -DDP or trans-DPP appears to indicate the ultimate survival of treated cells ... 

Again, as had been seen in L1210 cells, ISC peaked 6-12 hr following drug treatment, and DPC was a greater contributor to total crosslinking following trans-DPP compared with cis-DDP. 

Once again, at equitoxic concentrations of each agent, ISC was comparable whereas DPC was much greater in trans-DDP-treated cells. However, trans-DPP was virtually non-mutagenic (Figure... 

Trans-DPP has leaving groups stereochemlcally disposed to make the formation of crosslinks at adjoining base pairs within one strand of DNA (Intrastrand crosslinking) unlikely (see Figure... 

SCE formation probably derives from neither the mutagenic nor cytotoxic cls-DDP lesion. The non-mutagenlc trans-DPP can form SCE s. Immediate thiourea can only block SCE formation at very low cls-DDP doses and delaying thiourea allows almost total escape of SCE formation from thiourea blockade. DNA monoadduct formation may Induce SCE formation. What little effect thiourea does have on SCE formation may derive from thiourea s binding of unreacted. Intracellular Pt prior to Its binding to DNA at all. 

The identification of critical DNA lesions in cells could also aid in new drug development Analogs of promise could be compared with parent compounds in a manner similar to our comparison of cis- and trans-DPP as to DNA damage and its resultant effects An initial test of this approach vs animal screening could be made to see if similar results were obtained If so, the in vitro approach would be more rapid and less costly ... 

Platinum compounds without antitumor activity (17) such as t2 ons-DDP and [Pt(dien)Cl]Cl (Figure 1) covalently bind to DNA in vivo. Several studies have compared the biological effects which result when equal amounts of these three platinum compounds are fixed on DNA (typically r j 10" -10"6), Cis-DDP is 5-10 times more toxic toward E, ooli ( ) and mammalian cells (j, U.) than t2 ans-DDP, The relative toxicity is correlated with the ability of these two isomers to inhibit DNA replication (, i3, J 4). The ois isomer is repaired more efficiently by E, ooli W and is at least 750 times more mutagenic in mammalian cells (11) than the trans isomer. The compound [Pt(dien)Cl]Cl binds covalently to the DNA of E, ooli and seems not to be repaired nevertheless this compound does not inhibit DNA synthesis or kill the bacteria ( ), Repair of platinum compounds by E, ooli may be under the control of the SOS system c s-DDP induces 5-10 times more recA protein in treated E. Coli than an equal amount of trans-DPP or [Pt(dien)Cl]Cl fixed on the DNA (18), It seems that different modes of fixation on DNA are responsible for the different mutagenicity, toxicity and DNA repair of these platinum complexes. These results suggest that the antitumor activity of platinum(II) compounds may also depend on the formation of particular platinum-DNA lesions. 

For < 0.01, gis-DDP destabilizes DNA while trans-DPP and [Pt(dTen)CliCl stabilize DNA. Alteration of the melting tempera-ture of DNA by fixation of the three platinum compounds at low is shown in Figure 8, In all cases the changes in Tm were a linear function of the quantity of bound platinum For the fixation of 5 platinum per 1000 bases (30 platinum per T7 DNA molecule), trans-DDP and [Pt(dien)Cl]Cl increased the melting temperature by 0 7 C and 1,7 C respectively while ois-DDP decreased the Tm by 1,7 C ( ),... 

INTERACTION OF CIS- AND TRANS-DPP WITH SV40 DNA Effect of the Covalent Binding on ... 

In fact, DNA-platinum lesions created by trans-DPP are removed more rapidly than those created by cis-DDP (36,41,76), and this difference may be largely responsible for the difference in the biological activities of the two compounds. The trans isomer also undergoes aquation at a faster rate than the cis isomer, and... 

The differences revealed in the gel electrophoretic pattern of the nucleosome core particle after binding cis- and trans-DPP (10) could possibly provide a simple in vitro screen for pTatinum antitumor drug activity. Preliminary studies (12) have shown that nucleosome cores incubated with either dichloroethylenediamine-platinum(II) or cis-dichlorobis(isopropylamine)-platinum(II), two known antitumor drugs, exhibit gel electrophoretic patterns very similar to those of nucleosome cores incubated with cis-DDP. Incubation with [(terpy)PtCl]Cl, an inactive compound, gave very different gel patterns. Further work is in progress to evaluate the utility of this assay. 

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