PubMed Health⌕ Search

Biomedical subjects

V Brabec

Publications and source records attributed to V Brabec.

At least 37 records · Page 2Linked to original sources
PubMed1999

DNA interactions of new antitumor aminophosphine platinum(II) complexes.

Mechanistic studies are presented of a novel class of aminophosphine platinum(II) complexes as potential anticancer agents. These new agents, which have demonstrated activity against murine and human tumor cells including those resistant to cisplatin are cis-[PtCl2(Me2N(CH2)3PPh2-P)2] (Com1) and cis-[PtCl(C6H11NH(CH2)2PPh2-N,P)(C6H11NH(CH2) 2PPh2-P)] (Com2). We studied modifications of natural and synthetic DNAs in cell-free media by Com1 and Com2 by various biomedical and biophysical methods and compared the results with those obtained when DNA was modified by cisplatin. The results indicated that Com1 and Com2 coordinated to DNA faster than cisplatin. Bifunctional Com1 formed DNA adducts coordinating to single adenine or guanine residues or by forming cross-links between these residues. In comparison with cisplatin, Com1 formed the adducts more frequently at adenine residues and also formed fewer bidentate lesions. The monofunctional Com2 only formed DNA monodentate adducts at guanine residues. In addition, Com1 terminated DNA synthesis in vitro more efficiently than cisplatin whereas Com2 blocked DNA synthesis only slightly. DNA unwinding studies, measurements of circular dichroism spectra, immunochemical analysis, and studies of the B-Z transition in DNA revealed conformational alterations induced by the adducts of Com1, which were distinctly different from those induced by cisplatin. Com2 had little influence on DNA conformation. It is suggested that the activity profile of aminophosphine platinum(II) complexes, which is different from that of cisplatin and related analogs, might be associated with the specific DNA binding properties of this new class of platinum(II) compounds.

Antineoplastic Agents↗
PubMed1999

[Silent forms of hereditary spherocytosis].

We report 7 cases of "silent" form of hereditary spherocytosis observed among members of 4 different families. Silent form of hereditary spherocytosis occurred in 5.4% of all patients with hereditary spherocytosis treated in our institute. The patients with silent form featured normal Hb level and red blood cell count, normal or slightly elevated reticulocyte count and bilirubin level. Osmotic resistance of red blood cells was decreased and autohemolysis was increased, nevertheless, the differences from normal range were less prominent than in patients with manifest form of the disease. Analysis of red cell membrane revealed deficiency of band 3 protein in all cases of silent form of hereditary spherocytosis.

Adolescent↗
PubMed1999

[Clinical importance of determining levels of circulating transferrin receptors in blood].

Circulating serum transferrin receptor level was measured using mouse monoclonal antibody against transferrin receptor (Orion Diagnostica, Finland) in 126 patients with various disorders of erythropoiesis and the results were compared to those obtained form control group consisted of 30 healthy volunteers with normal iron stores. Serum transferrin receptor level was significantly elevated in patients with iron deficiency and in all patients with hyperplastic erythropoiesis (hereditary spherocytosis, immune hemolytic anemia, beta thalassemia, myelodysplasia). Measurement of circulating serum transferrin receptor level was a sensitive indicator of iron depletion as well as a helpful parameter in differential diagnosis between iron deficiency and anemia of chronic disease where circulating transferrin receptor level was not elevated. Index transferrin receptor/ferritin calculated as a ratio of circulating serum transferrin receptor level to log serum ferritin level was a more sensitive parameter than measurement of serum transferrin receptor not only for determination of patients with anemia of chronic disease, but also for discrimination of patients with elevated serum transferrin receptor level due to true iron deficiency from those with high serum transferrin receptor level caused by relative iron deficiency in hyperplastic erythropoiesis.

Diagnosis, Differential↗
PubMed1999

[Pregnancy in patients with hereditary spherocytosis].

The influence of pregnancy on the course of hereditary spherocytosis was investigated in 21 women during their 44 pregnancies. Fourteen pregnancies were followed up directly, 30 were evaluated from anamnestic data. In the majority of investigated women with hereditary spherocytosis pregnancy caused no problems. When complications developed, they were not serious as a rule. Only about one third of pregnancies in non-splenectomized women developed anaemia or anaemia deteriorated. In the latter enhanced haemolysis participated. In splenectomized patients the incidence of complaints was minimal.

Female↗
PubMed1998

DNA interactions of antitumor trans-[PtCl2(NH3)(quinoline)].

Recent observations that several trans-platinum complexes exhibit antitumor activity including activity in cisplatin-resistant tumor cells, violates the classical structure/activity relationships of platinum(II) complexes. According to these relationships, only bifunctional platinum(II) complexes with cis-oriented leaving ligands should be therapeutically active. In order to contribute to the understanding of mechanisms underlying the antitumor activity of these new trans-platinum analogs, various biochemical and biophysical methods as well as molecular modeling techniques were employed to study the modifications of DNA by antitumor trans-[PtCl2(NH3)(quinoline)]. The results indicated that trans-[PtCl2(NH3)(quinoline)] coordinated monofunctionally to DNA with a similar rate as transplatin. The overall rate of the rearrangement to bifunctional adducts was also similar to that observed in the case of DNA modification by transplatin, i.e. it was relatively slow (after 48 h approximately 34% adducts remained monofunctional). In contrast to transplatin, however, trans-[PtCl2(NH3)(quinoline)] formed considerably more interstrand cross-links after 48 h (approximately 30%) with a much shorter half-time (approximately 5 h) (approximately 12% for transplatin, t1/2 > 11 h). The results also suggested that the quinoline ligand in all or in a significant fraction of DNA adducts of trans-[PtCl2(NH3)(quinoline)], in which platinum is coordinated to base residues, was well positioned to interact with the duplex. The adducts of trans-[PtCl2(NH3)(quinoline)] terminated in vitro RNA synthesis preferentially at guanine residues. Surprisingly, the type and extent of conformational alterations induced in DNA indicates that trans-[PtCl2(NH3)(quinoline)] behaves in some respects like cisplatin, as indicated by the fact that trans-[PtCl2(NH3)(quinoline)]-modified DNA is recognized by cisplatin-specific antibodies. Models for both monofunctional adducts and bifunctional interstrand cross-links are proposed. Computer-generated AMBER models show that the combination of monofunctional covalent binding and a stacking interaction between quinoline and the DNA bases can produce a kink in the duplex which is strongly suggestive of the directed bend produced by the major cisplatin-DNA adduct (1,2 intrastrand cross-link). Unique DNA adducts of this type formed by trans-[PtCl2(NH3)(quinoline)] may contribute to the antitumor efficacy of this agent.

Animals↗
PubMed1998

[Haplotypes of the beta-globulin locus in Czechs and Slovaks with beta-thalassemia and structurally variant hemoglobins].

In 29 Czech and Slovak families with the most frequent and newly identified beta-thalassaemic alleles and with some structural haemoglobin variants (Hb E, Hb Haná, Hb Santa Ana) haplotypes of the beta-globin locus of alleles with these mutations were identified. In most instances haplotypes I and V were involved which were found in 57% of the patients. The bond of the most common beta-thalassaemic mutation: IVS-I-1, IVS-I-110, CD 39 (C-T), IVS-II-745, IVS-I-6 with alleles with the same haplotypes as in the mediterranean region suggests a mediterranean origin of these mutations. In Hb Santa Ana a hitherto not described haplotype was identified (-(+)-(-)-(+3), indicating a de novo origin of the mutation. Also in newly identified beta-thalassaemic mutations in CD 7/8 (+G), in CD 38/39 (-C) and in HbE and Hb Haná de novo development is probable.

Czech Republic↗
PubMed1998

DNA interactions of a novel platinum drug, cis-[PtCl(NH3)2(N7-acyclovir)]+.

We synthesized a novel platinum drug, cis-[PtCl(NH3)2(N7-ACV)]+, in which ACV is the antiviral drug acyclovir [a deoxyriboguanosine analogue, 9-(2-hydroxyethoxymethyl)guanine]. This new compound exhibits antiviral efficacy in vitro and exhibits an antitumor activity profile different from that of cisplatin [Metal-Based Drugs 2:249-256 (1995)]. To contribute to understanding the mechanisms underlying biological activity of this new compound, we studied modifications of natural and synthetic DNAs in cell-free media by cis-[PtCl(NH3)2(N7-ACV)]+ by various biochemical and biophysical methods. The results indicated that the major DNA adduct of cis-[PtCl(NH3)2(N7-ACV)]+ was a stable monofunctional adduct at guanine residues. In contrast to DNA adducts of other monodentate and clinically ineffective platinum(II) compounds, the adducts of cis-[PtCl(NH3)2(N7-ACV)]+ terminated in vitro DNA and RNA synthesis. In addition, although DNA adducts of cis-[PtCl(NH3)2(N7-ACV)]+ and cisplatin were different, some properties of DNA modified by either compound were qualitatively similar. Such similarities were not noticed if DNA modifications by other ineffective monofunctional platinum(II) complexes were investigated. Thus, the DNA binding mode of monofunctional cis-[PtCl(NH3)2(N7-ACV)]+ was different from that of other monofunctional but ineffective platinum(II) complexes. It has been suggested that the unique capability of cis-[PtCl(NH3)2(N7-ACV)]+ to modify DNA may be relevant to a distinct antitumor efficiency of this novel drug in comparison with cisplatin. It also has been suggested that at least some aspects of DNA interactions of cis-[PtCl(NH3)2(ACV)]+ revealed in the current study could be exploited in the search for and development of new antiviral platinum complexes containing, as a part of the coordination sphere, antiviral nucleosides.

Acyclovir↗
PubMed1997

Characterization of the underlying molecular defect in hereditary spherocytosis associated with spectrin deficiency.

Several subsets of patients with hereditary spherocytosis (HS) have been defined based on the specific red blood cell membrane protein deficiencies involving spectrin, ankyrin, band 3, and protein 4.2. Mutations of the genes encoding these proteins are currently being uncovered. Regarding spectrin, only three isolated cases of beta-spectrin gene mutations were recently reported in association with HS and spectrin deficiency. We have screened the coding region of the beta-spectrin gene using the SSCP technique, in 40 families with HS associated with spectrin deficiency or combined spectrin and ankyrin deficiencies. In this report we describe six frameshift and nonsense mutations and four missense mutations of the beta-spectrin gene in 11 unrelated families. Taking advantage of modifications in the restriction enzyme recognition sequences introduced by the mutations, we show, in all cases of frameshift and nonsense mutations, the loss of heterozygosity at the cDNA level when compared to genomic DNA, reflecting the absence of the mutant mRNA transcripts. In one family with a large pedigree including six generations and 112 members, we firmly establish the autosomal dominant inheritance of one of the beta-spectrin null mutations. Most of the mutations described are responsible for a phenotype of mild to moderate autosomal dominant form of HS associated with a conspicuous spherocytosis with frequent spiculated cells (8% to 15% acanthocytes). One missense mutation appears to be associated with a recessive form of the disease. Five common restriction enzyme polymorphisms of the coding region of the beta-spectrin gene are also described. Overall, these findings underscore the importance of the beta-spectrin gene mutations in the pathogenesis of HS and reemphasizes the extreme heterogeneity of the underlying molecular basis of this condition.

DNA, Complementary↗
PubMed1997

DNA interactions of bifunctional dinuclear platinum(II) antitumor agents.

Modifications of natural DNA in a cell-free medium by dinuclear bisplatinum complexes with equivalent coordination spheres, represented by the general formula [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+, where R is a propane or hexane, were studied by various methods of biochemical analysis or molecular biophysics. These methods include binding studies by means of differential-pulse polarography, measurements of melting curves with the aid of absorption spectrophotometry, measurements of CD spectra, ELISA with specific antibodies that recognize DNA modified by platinum complexes, interstrand cross-linking assay employing gel electrophoresis under denaturing conditions and mapping of DNA adducts by means of transcription assays. The results indicated that the major adduct of [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ in DNA was an interstrand cross-link which was formed with a relatively short half-time (approximately 1 h). At least some types of these interstrand cross-links induced local denaturational changes in the DNA. The results of analyses of interactions of [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ with linear DNA at relatively higher levels of the modification could be interpreted to mean that these dinuclear platinum complexes were also capable of intrastrand-cross-link formation between adjacent base residues in DNA. However, these intrastrand adducts of [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ distorted DNA conformation in a way different from the DNA intrastrand adducts of cisplatin. In addition, the DNA adducts of the dinuclear platinum complexes inhibited DNA transcription in vitro. The length of the aliphatic linker chain affected the DNA-binding mode of [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ and the resulting conformational changes in DNA. The extensive analysis of DNA interactions with [¿trans-PtCl(NH3)2¿2(H2N-R-NH2)]2+ described in this communication has provided further experimental support for previous suggestions [Farrell, N. (1991) in Platinum and other metal coordination compounds in cancer chemotherapy (Howell, S. B., ed.) pp. 81-91, Plenum Press, New York] that the binding of the dinuclear platinum complexes modifies DNA in a way that is different from the modification by antitumor cisplatin. Thus, the results of this work are consistent with the hypothesis that platinum drugs that bind to DNA in a manner fundamentally different from that of cisplatin can exhibit altered biological properties, including a different spectrum and intensity of antitumor activity.

Animals↗
PubMed1997

Incomplete distal renal tubular acidosis coinherited with a mutation in the band 3 (AE1) gene.

BACKGROUND: Band 3 (anion exchanger 1, AE1) is one of the most abundant proteins of the erythrocyte membrane. We have previously characterized twenty AE1 gene defects underlying spherocytic haemolytic anaemia with band 3 deficiency. Since AE1 is also expressed in the intercalated cells of renal cortical collecting ducts where it is thought to participate in urine acidification, we asked whether the spherocytogenic AE1 mutations also affect the regulation of urine acidity. METHODS: We examined 10 patients from seven unrelated families with hereditary spherocytosis with band 3 deficiency using the short urine acidification test with CaCl2 administration at a dose of 0.2 g/kg b.w. To asses the ability of the nephron to secrete protons, 400 ml of NaHCO3 were infused over a period of 2 h. RESULTS: While we detected no significant abnormalities in eight patients, we have diagnosed incomplete distal renal tubular acidosis (dRTA) in two patients from one family whose urinary pH 5 h after CaCl2 administration were 6.56 and 6.89. Administration of bicarbonate in these two patients resulted in high urinary HCO3- concentration. The patients carry the previously characterized mutation band 3PRIBRAM that encodes a C-terminally truncated band 3 containing only the cytoplasmic domain and the first three putative transmembrane segments. CONCLUSIONS: This finding shows an association of a band 3 defect with abnormal urinary acidification perhaps secondary to Cl-/HCO3- exchange in the basolateral membrane of alpha-intercalated cells of cortical collecting ducts.

Acidosis↗
PubMed1997

DNA modifications by antitumor trans-[PtCl2(E-iminoether)2].

Recent findings that an analogue of clinically ineffective transplatin, trans-[PtCl2(E-iminoether)2], exhibits antitumor activity has helped reevaluation of the empirical structure-antitumor activity relationship generally accepted for platinum(II) complexes. According to this relationship, only the cis geometry of leaving ligands in the bifunctional platinum(II) complexes, should be therapeutically active. Global modifications of natural DNAs in cell-free media by trans-[PtCl2(E-iminoether)2] were studied through various molecular biophysical methods and compared with modifications by cis-[PtCl2(E-iminoether)2], transplatin, cisplatin, and monofunctional chlorodiethylenetriamineplatinum(II) chloride. Thus, the results of this study have extended our recent finding, indicating that the prevalent lesion occurring in double-helical DNA on its modification by trans-[PtCl2(E-iminoether)2] is a monofunctional adduct at guanine residues. The modification by trans-[PtCl2(E-iminoether)2] has been found to induce local distortions in DNA, which have a character differing fundamentally from those induced by both clinically ineffective or antitumor platinum complexes tested in this study. The different character of alterations induced in DNA by the adducts of trans-[PtCl2(E-iminoether)2] and transplatin has been suggested to be relevant to the unexpected observation that the new complex with leaving chloride groups in trans position exhibits antitumor efficacy. In addition, the results support the idea that platinum drugs that bind to DNA in a manner fundamentally different from that of cisplatin can exhibit altered biological properties, including differing spectra and intensities of antitumor activity.

Animals↗
PubMed1997

The effect of antitumor trans-[PtCl2(E-iminoether)2] on B-->Z transition in DNA.

The B-->Z transition of DNA modified by platinum(II) complexes has attracted considerable interest because of a possible relationship with the molecular mechanism of antitumor activity of these metal-based compounds. Until recently it was generally accepted that the cis geometry of leaving groups in the bifunctional platinum(II) complexes should be therapeutically active. This paradigm had to be abandoned recently due to the finding that several analogues of clinically ineffective trans-diamminedichloroplatinum(II) (transplatin) exhibit antitumor activity. One of these therapeutically active trans compounds is trans-dichlorobisiminoetherplatinum(II) (trans-EE) [iminoether = E-HN = C(OMe)Me]. In view of the fact that DNA is the main pharmacological target for platinum(II) complexes and that these complexes attack preferentially guanine residues in DNA, it is of interest to examine the effect of iminoether platinum(II) complexes on the conformation of double-stranded poly(dG-dC) and its synthetic analogues. As these polymers can undergo the B-->Z transition, we have investigated in detail the effect of trans-EE and its cis isomer (cis-EE) on this conformational transformation using different techniques. They include circular dichroism spectroscopy, Raman spectroscopy and immunochemical assay employing specific antibodies against Z-DNA. It has been shown that cis-EE somewhat facilitates the B-->Z transition induced by increasing NaCl concentration and radically lowers its cooperativity. The polymers modified by cis-EE at low or high salt concentrations have been found to adopt distorted conformations which belong to the B and Z families respectively. Thus, cis-EE affects the B-->Z transition in DNA in a way similar to antitumor cis-diamminedichloroplatinum(II) (cisplatin). On the other hand, trans-EE was found to affect B-->Z transition (its cooperativity or the NaCl concentration corresponding to the midpoint of the salt-induced transition) only slightly. This behavior of trans-EE was, however, fundamentally different from that of clinically ineffective transplatin, which hinders B-->Z transition and lowers its cooperativity. The different effects of trans-EE on the B-->Z transition in comparison with the effects of cisplatin, transplatin and monofunctional chlorodiethylenetriamineplatinum(II) chloride are consistent with a unique DNA binding mode of this new antitumor trans compound, which might be associated with its unexpected biological efficacy.

Antibody Affinity↗
PubMed1997

[Relation between types of erythrocyte membrane defects and the clinical picture in hereditary spherocytosis].

From total number of 130 patients with hereditary spherocytosis from 75 families in 119 patients from 69 families a defect of membrane proteins was detected. In 23 families (33.3%) a spectrin defect was involved, in 32 families (46.3%) a combined defect of spectrin and ancyrine and in 14 families (20.3%) a defect of band 3 proteins. Investigation of the membrane defect and the clinical and laboratory picture revealed that the band 3 protein defect of spectrin and ancyrine. There are significant differences in the clinical picture of the two latter defects.

Adult↗
PubMed1996

Site-specific d(GpG) intrastrand cross-links formed by dinuclear platinum complexes. Bending and NMR studies.

The novel platinum drugs [{trans-PtCl(NH3)2}2H2N(CH2)nNH2]2+ (1,1/t,t) are currently undergoing preclinical development. The bifunctional DNA binding of these agents allows comparison with that of cisplatin [Farrell et al. (1995) Biochemistry, 34, 15480]. The major DNA lesion of cisplatin, the 1,2-d(GpG) intrastrand adduct, produces a rigid, directed bend 30-35 degrees into the major groove of DNA. We have now completed a structural analysis of the corresponding adduct formed with the dinuclear complexes. Gel retardation assays on 15-22 bp oligonucleotides containing a central d(TG*G*T) site show that the (Pt,Pt)-intrastrand adducts result in a flexible nondirectional bend. This bend is essentially independent of chain length (n = 2, 4, 6). Chemical reactivity assays indicated a hypersensitivity of the thymine 5' to the adduct and an enhanced sensitivity of the 3'-thymine to OsO4. 2D 1H NMR studies on a d(TG1G2T) adduct of [{trans-PtCl(NH3)2}2H2N(CH2)6NH2]2+ have delineated the structural features responsible for these observations. In contrast to the cisplatin adduct, which displays a 100% N-type sugar of the 5'-G and an anti base conformation of the platinated bases in both solid state and solution, the dinuclear adduct does not display the typical N-type sugar pucker. The base orientations are anti (5'-T), anti (G1), anti/syn (G2), and anti (3'-T) while the sugar conformations are N, S/N, N, and S, respectively. The 5'-T remains stacked with its guanine neighbor while the 3'-T becomes unstacked, a reverse of the situation observed for cis-DDP.

Antineoplastic Agents↗
PubMed1996

Characterization of 13 novel band 3 gene defects in hereditary spherocytosis with band 3 deficiency.

Hereditary spherocytosis (HS) is a common hemolytic anemia of variable clinical expression. Pathogenesis of HS has been associated with defects of several red cell membrane proteins including erythroid band 3. We have studied erythrocyte membrane proteins in 166 families with autosomal dominant HS. We have detected relative deficiency of band 3 in 38 kindred (23%). Band 3 deficiency was invariably associated with mild autosomal dominant spherocytosis and with the presence of pincered red cells in the peripheral blood smears of unsplenectomized patients. We hypothesized that this phenotype is caused by band 3 gene defects. Therefore, we screened band 3 DNA from these 38 kindred for single strand conformational polymorphisms (SSCP). In addition to five mutations detected previously by SSCP screening of cDNA, we detected 13 new band 3 gene mutations in 14 kindred coinherited with HS. These novel mutations consisted of two distinct subsets. The first subset included seven nonsense and frameshift mutations that were all associated with the absence of the mutant mRNA allele from reticulocyte RNA, implicating decreased production and/or stability of mutant mRNA as the cause of decreased band 3 synthesis. The second group included five substitutions of highly conserved amino acids and one in-frame deletion. These six mutations were associated with the presence of comparable levels of normal and mutant band 3 mRNA. We suggest that these mutations interfere with band 3 biosynthesis leading thus to the decreased accumulation of the mutant band 3 allele in the plasma membrane.

Alleles↗
PubMed1996

Superhelical torsion controls DNA interstrand cross-linking by antitumor cis- diamminedichloroplatinum(II).

Negatively supercoiled, relaxed and linearized forms of pSP73 DNA were modified in cell-free medium by cis-diamminedichloroplatinum(II) (cisplatin). The frequency of interstrand cross-links (ICLs) formed in these DNAs has been determined by: (i) immunochemical analysis; (ii) an assay employing NaCN as a probe of DNA ICLs of cisplatin; (iii) gel electrophoresis under denaturing conditions. At low levels of the modification of DNA (<1 Pt atom fixed per 500 bp) the number of ICLs formed by cisplatin was radically enhanced in supercoiled in comparison with linearized or relaxed DNA. At these low levels of modification, the frequency of ICLs in supercoiled DNA was enhanced with increasing level of negative supercoiling or with decreasing level of modification. In addition, the replication mapping of DNA ICLs of cisplatin was consistent with these lesions being preferentially formed in negatively supercoiled DNA between guanine residues in both the 5'-d(GC)-3' and the 5'-d(CG)-3' sites. Among the DNA adducts of cisplatin the ICL has the markedly greatest capability to unwind the double helix. We suggest that the formation of ICLs of cisplatin is thermodynamically more favored in negatively supercoiled DNA owing mainly to the relaxation of supercoils.

Antineoplastic Agents↗
PubMed1996

The effect of ionic strength on melting of DNA modified by platinum(II) complexes.

Thermal denaturation of calf thymus DNA modified by antitumor cis-diamminedichloroplatinum(II) (cis-DDP) and by two related Pt(II) compounds which had been shown to be clinically ineffective, viz. trans-diamminedichloroplatinum(II) (trans-DDP) or monodentate diethylenetriaminechloroplatinum(II) chloride [[Pt(dien)Cl)]Cl], was studied by monitoring changes of absorbance at 260 nm. The melting of DNA platinated to different levels was investigated in neutral media containing varying concentrations of Na+. It has been shown that the ionic strength has a strong influence on the character and magnitude of changes in the melting temperature of DNA (Tm) induced by the platination. The modification of DNA by either platinum complex used in this work results in an increase of Tm if DNA melting is measured in media containing low Na+ concentrations (ca. 1 mM). This effect is reversed at higher Na+ concentrations. The concentration of Na+ at which this reversal occurs is, however, markedly lower for DNA modified by cis-DDP than for DNA modified by the other two platinum complexes. These results have been interpreted to mean that at least three factors affect the thermal stability of DNA modified by the platinum(II) complexes: stabilization effects of the positive charge on the platinum moiety and of interstand cross-links, and a destabilization effect of conformational distortions in DNA. Thus, in order to compare and interpret the melting behavior of DNA modified by different compounds, a great attention has to be paid to the composition of the medium in which the melting experiments are carried out.

Animals↗