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N Farrell

Publications and source records attributed to N Farrell.

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

Sequence-dependent conformational changes in DNA induced by polynuclear platinum complexes.

In this work, the B-->Z transition of poly(dG-dC).poly(dG-dC) and the B-->A transition of poly(dG).poly(dC) and of calf thymus (CT) DNA fragments modified by antitumor bifunctional polynuclear platinum complexes were investigated by circular dichroism (CD). The transition from the B- to Z-form of DNA was inducible with all three compounds studied, as indicated by an inversion of the B-form spectra. The B-->A transition in poly(dG).poly(dC) was induced easily by platinum complex binding alone, while the B-->A transition in CT DNA was induced by ethanol but inhibited by coordination of all polynuclear platinum compounds used here. It was shown that the compound [¿cis-PtCl(NH3)2¿2 mu-¿H2N(CH2)6NH2¿] (NO3)2 (1,1/c,c) was most effective at inhibiting the B-->A transition in CT DNA, and [¿trans-PtCl(NH3)2¿2 mu-¿trans-Pt(NH3)2(H2N(CH2)6NH2)2¿] (NO3)4 (1,0,1/t,t,t) was least effective, while the effectiveness of [¿trans-PtCl(NH3)2¿2 mu-¿H2N(CH2)6NH2¿] (NO3)2 (1,1/t,t) fell between the two. This corresponded to the relative amounts of interstrand crosslinks in double-stranded DNA caused by each compound.

Animals↗
PubMed1999

Comparison of cytotoxicity and cellular accumulation of polynuclear platinum complexes in L1210 murine leukemia cell lines.

The antitumor activity of the trinuclear Phase I clinical agent, BBR3464, is matched by that of polyamine-linked dinuclear complexes. The cytotoxicity and cellular accumulation of three polynuclear platinum complexes: [¿trans-PtCl(NH3)2¿2 mu-¿trans-Pt(NH3)2(H2N(CH2)6-NH2)2¿]4+ (BBR3464), [¿trans-PtCl(NH3)2¿2(H2N(CH2)3NH2(CH2)4NH2)]3+ (BBR3571), and [¿trans-PtCl(NH3)2¿2(H2N(CH2)6-NH2)]2+ (BBR3005), were studied in a series of murine L1210 cell lines and compared with cisplatin. Besides murine L1210 cell lines sensitive (/0) and resistant (/DDP) to cisplatin, the efficacy of the compounds in a cell line rendered resistant to BBR3464 (/3464) was examined. Finally, to examine possible uptake pathways of these novel charged complexes, cytotoxicity in a cell line resistant to the polyamine synthesis inhibitor, methylglyoxal-bis(guanylhydrazone) (/MGBG), was studied. Cytotoxicity profiles of BBR3571 most closely matched that of BBR3464. Both agents showed significantly reduced cytotoxicity in L1210/ BBR3464. The cytotoxicity of neither agent was affected by the polyamine uptake-deficient cell line and indeed both complexes showed significantly enhanced cytotoxicity in L1210/MGBG relative to wild-type L1210/0. The cellular uptake of both BBR3464 and BBR3571 was enhanced in L1210/DDP. These studies suggest that the chemical feature of a diamine linker containing an internal charge contributes significantly to the anticancer profiles of both the trinuclear platinum complex, BBR3464, which incorporates a charged platinum into a diamine linker, and the dinuclear platinum complex, BBR3571, which incorporates only a naturally occurring polyamine as diamine linker.

Animals↗
PubMed1999

The cellular basis of the efficacy of the trinuclear platinum complex BBR 3464 against cisplatin-resistant cells.

Multinuclear platinum compounds have been designed to circumvent the cellular resistance to conventional mononuclear platinum-based drugs. In this study we performed a comparative study of cisplatin and of the triplatinum complex BBR 3464 in a human osteosarcoma cell system (U2-OS) including an in vitro selected cisplatin-resistant subline (U2-OS/Pt). BBR 3464 was extremely potent in comparison with cisplatin in U2-OS cells and completely overcame resistance of U2-OS/Pt cells. In both cell lines, BBR 3464 accumulation and DNA-bound platinum were higher than those observed for cisplatin. On the contrary, a low frequency of interstrand cross-links after exposure to BBR 3464 was found. Differently from the increase of DNA lesions induced by cisplatin, kinetics studies indicated a low persistence of interstrand cross-link formation for BBR 3464. Western blot analysis of DNA mismatch repair proteins revealed a marked decrease of expression of PMS2 in U2-OS/Pt cells, which also exhibited microsatellite instability. Studies on DNA mismatch repair deficient and proficient colon carcinoma cells were consistent with a lack of influence of the DNA mismatch repair status on BBR 3464 cytotoxicity. In conclusion, the cytotoxic potency and the ability of the triplatinum complex to overcome cisplatin resistance appear to be related to a different mechanism of DNA interaction (formation of different types of drug-induced DNA lesions) as compared to conventional mononuclear complexes.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Cellular pharmacology of polynuclear platinum anti-cancer agents.

Study of the cellular pharmacology of the dinuclear platinum complexes, BBR3005 ([¿trans-PtCl(NH3)2¿2H2N(CH2)6NH2]2+), BBR3171 ([¿cis-PtCl(NH3)2¿2H2N(CH2)6NH2]2+) and the trinuclear platinum complex, BBR3464 ([¿trans-PtCl(NH3)2¿2 mu-¿trans-Pt(NH3)2(H2N(CH2)6NH2)2¿]4+) was undertaken in wild type and cisplatin-resistant L1210 murine leukemia cell lines. All complexes are potent cytotoxic agents against the wild type cell line. Only BBR3464 shows enhanced activity against the cisplatin-resistant cell line following a brief exposure. This enhanced activity is attributable, in part, to preserved accumulation, which contrasts with diminished accumulation of cisplatin and both dinuclear platinum complexes. The cisplatin-resistant cell line is relatively tolerant of DNA adducts induced by both cisplatin and BBR3464, but BBR3464 is much less affected. All complexes induce DNA interstrand cross-links. Di/trinuclear complex-induced interstrand cross-linking peaks early, suggesting rapid genomic access and interaction. Subsequent decay suggests susceptibility to DNA repair mechanisms. Peak and area-under-the-curve values for interstrand cross-linking among the complexes correlate poorly with cytotoxic effects, especially in the cisplatin-resistant cell line. This suggests that all interstrand cross-linking adducts are not equal in their cytotoxic effect, or other, non-interstrand cross-linking adducts are significant. BBR3464 has been selected for clinical development largely on the basis of results from in vivo activity and toxicity studies. These results show BBR3464 to have unique properties in the context of acquired cisplatin-resistance that enhance its candidacy as a potential anticancer agent.

Animals↗
PubMed1999

A novel charged trinuclear platinum complex effective against cisplatin-resistant tumours: hypersensitivity of p53-mutant human tumour xenografts.

Multinuclear platinum compounds were rationally designed to bind to DNA in a different manner from that of cisplatin and its mononuclear analogues. A triplatinum compound of the series (BBR 3464) was selected for preclinical development, since, in spite of its charged nature, it was very potent as cytotoxic agent and effective against cisplatin-resistant tumour cells. Anti-tumour efficacy studies were performed in a panel of human tumour xenografts refractory or poorly responsive to cisplatin. The novel platinum compound exhibited efficacy in all tested tumours and an impressive efficacy (including complete tumour regressions) was displayed in two lung carcinoma models, CaLu-3 and POCS. Surprisingly, BBR 3464 showed a superior activity against p53-mutant tumours as compared to those carrying the wild-type gene. The involvement of p53 in tumour response was investigated in an osteosarcoma cell line, SAOS, which is null for p53 and is highly sensitive to BBR 3464, and in the same cells following introduction of the wild-type p53 gene. Thus the pattern of cellular response was investigated in a panel of human tumour cells with a different p53 gene status. The results showed that the transfer of functional p53 resulted in a marked (tenfold) reduction of cellular chemosensitivity to the multinuclear platinum complex but in a moderate sensitization to cisplatin. In addition, in contrast to cisplatin, the triplatinum complex was very effective as an inducer of apoptosis in a lung carcinoma cell line carrying mutant p53. The peculiar pattern of anti-tumour activity of the triplatinum complex and its ability to induce p53-independent cell death may have relevant pharmacological implications, since p53, a critical protein involved in DNA repair and induction of apoptosis by conventional DNA-damaging agents, is defective in several human tumours. We suggest that the peculiar DNA binding properties of the triplatinum complex may contribute to the striking profile of anti-tumour efficacy. Taken together, the available information supports that anti-tumour activity of the novel compound is mediated by a mechanism different from that of conventional platinum complexes, and compounds of this series could represent a new class of promising anti-tumour agents.

Animals↗
PubMed1999

A novel trinuclear platinum complex overcomes cisplatin resistance in an osteosarcoma cell system.

Multinuclear platinum compounds have been designed to circumvent the cellular resistance to conventional platinum-based drugs. In an attempt to examine the cellular basis of the preclinical antitumor efficacy of a novel multinuclear platinum compound (BBR 3464) in the treatment of cisplatin-resistant tumors, we have performed a comparative study of cisplatin and BBR 3464 in a human osteosarcoma cell line (U2-OS) and in an in vitro selected cisplatin-resistant subline (U2-OS/Pt). A marked increase of cytotoxic potency of BBR 3464 in comparison with cisplatin in U2-OS cells and a complete lack of cross-resistance in U2-OS/Pt cells were found. A detailed analysis of the cisplatin-resistant phenotype indicated that it was associated with reduced cisplatin accumulation, reduced interstrand cross-link (ICL) formation and DNA platination, microsatellite instability, and reduced expression of the DNA mismatch repair protein PMS2. Despite BBR 3464 charge and molecular size, in U2-OS and U2-OS/Pt cells, BBR 3464 accumulation and DNA-bound platinum were much higher than those observed for cisplatin. In contrast, the frequency of ICLs after exposure to BBR 3464 was very low. The time course of ICL formation after drug removal revealed a low persistence of these types of DNA lesions induced by BBR 3464, in contrast to an increase of DNA lesions induced by cisplatin, suggesting that components of the DNA repair pathway handle the two types of DNA lesions differently. The cellular response of HCT116 mismatch repair-deficient cells was consistent with a lack of influence of mismatch repair status on BBR 3464 cytotoxicity. Because BBR 3464 produces high levels of lesions different from ICLs, likely including intra-strand cross-links and monoadducts, the ability of the triplatinum complex to overcome cisplatin resistance appears to be related to a different mechanism of DNA interaction (formation of different types of drug-induced DNA lesions) as compared with conventional mononuclear complexes rather than the ability to overcome specific cellular alterations.

Antineoplastic Agents↗
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

Investigation of the trans effect in the fragmentation of dinuclear platinum complexes by electrospray ionization surface-induced dissociation tandem mass spectrometry.

Cis and trans isomers of two dinuclear platinum complexes, [cis-¿Pt(NH3)2Cl¿2 mu-(NH2(CH2)nNH2)](NO3)2 (1,1/c,c) and [trans-¿Pt(NH3)2Cl¿2 mu-(NH2(CH2)nNH2)](NO3)2 (1,1/t,t), where the diamine was 1,4-butanediamine (n = 4) or 1,6-hexanediamine (n = 6), were studied using electrospray ionization surface-induced dissociation (ESI/SID) tandem mass spectrometry (MS/MS). The same fragment ions were observed for both the cis and trans isomers of each complex (n = 4 or 6), but the relative intensities were dependent on the isomer studied. The ESI/SID data and energy-resolved mass spectra show that the position of the chloride plays a significant role in the fragmentation of these ions. Two major fragmentation pathways were detected for the complexes. The cleavage of the Pt-N bond trans to chloride was the most favorable pathway for both isomers of the complexes following the ion-surface collision. The differences in the ESI/SID spectra between the cis and trans isomers can be explained by the trans effect, namely that the Pt-N bond trans to chloride is the most labile bond.

Diamines↗
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

Effect of geometric isomerism in dinuclear platinum antitumour complexes on the rate of formation and structure of intrastrand adducts with oligonucleotides.

The dinuclear platinum complexes [[trans -PtCl (NH3)2]2[mu]-[NH2(CH2) n NH2]](NO3)2[1,1/t,t ( n = 4,6)] and [[cis-PtCl(NH3)2]2[mu];-[NH2(CH2) n NH2](NO3) 2[1,1/c,c ( n = 4,6)] exhibit antitumour activity comparable with cisplatin. 1,1/c,c complexes do not form 1,2 GG intrastrand adducts, the major adduct of cisplatin, with double-stranded DNA. This 1H NMR spectroscopy study shows that, in the absence of a complementary strand, 1,1/c,c ( n = 4,6) form a 1,2 GG (N7, N7) intrastrand adduct with r(GpG), d(GpG) and d(TGGT). Initial binding to r(GpG) (and also reaction with GMP) at 37 degrees C was slower for 1,1/c,c compared with 1,1/t,t, whereas the second binding step (adduct closure) was faster for 1,1/c,c. However, the 1H NMR spectra of the 1,1/c,c adducts at 37 degrees C show two H8 signals, one of which is broad and becomes sharper on increasing the temperature, indicating restricted rotation around the Pt-N7 bond. For the d(GpG)-1,1/c,c ( n = 4) adduct, 2D NMR spectroscopy assigned the broad H8 signal to the 3' G, which has syn base orientation and 60% S-type/40% N-type sugar conformation. The 5' G has anti base orientation and S-type sugar conformation. Apart from the restricted rotation around the 3' G, the structure is similar to that of 1,2 GG intrastrand adducts of 1,1/t,t. This steric hindrance may explain the inability of 1,1/c,c complexes to form 1,2 GG intrastrand adducts with sterically more demanding double-stranded DNA.

Acetylcysteine↗
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

A circular dichroism study of ethidium bromide binding to Z-DNA induced by dinuclear platinum complexes.

Dinuclear bis(platinum) complexes have been shown previously to induce the B-->Z transition in synthetic DNAs (Nucleic Acids Res. 7, 1697-1703, J. Inorganic Biochem. 54, 207-220). In this paper, the reversibility of the Z conformation back to the B form was assessed by treatment of the induced Z form in poly(dG-dC).poly(dG-dC) with ethidium bromide (Etd). Z-DNA induced by the tetra-amine cations [{Pt(NH3)3}2(H2N(CH2)nNH2)]4+, which are capable of only electrostatic interactions with the polynucleotide, was readily reversible. The spectroscopic data mirrored that of ethidium bromide/poly(dG-dC).poly(dG-dC) in the presence of 4.4 M NaCl. In contrast, Z-DNA induced by the bifunctional complexes [{trans-PtCl(NH3)2}2(H2N(CH2)nNH2)]2+ did not produce spectra typical of Etd intercalation and reversal to B-form DNA. The original Z-form CD spectra of DNA treated with the bifunctional complexes could be reobtained following removal of Etd by extensive dialysis. The bifunctional complexes are very effective interstrand cross-linking agents. The data suggest that interstrand cross-linking by dinuclear complexes can stabilize or "lock" the Z-conformation prohibiting its reversal to the B-form. The implications for the biological activity of the dinuclear complexes are briefly discussed.

Circular Dichroism↗
PubMed1996

Immunocytochemical labelling of aerobic and hypoxic mammalian cells using a platinated derivative of EF5.

The monoclonal antibody ELK3-51 was previously developed to detect adducts of the 2-nitroimidazole EF5. Direct immunofluorescence was used to detect adducts of EF5 or of a platinated derivative cis-[PtCl2(NH3)EF5] in SCCVII cells treated under aerobic or hypoxic conditions. Fluorescence measurements of these cells using both image and flow cytometric methods were compared, giving similar profiles. Platination significantly decreased immunofluorescence levels (approximately 4-fold less than EF5) after 3 h in hypoxia, but also increased levels after exposure in air (approximately 1.5 x) such that the hypoxic ratio decreased from approximately 50 to approximately 13. Platinated EF5 also showed significantly greater cytotoxicity than its parent in both aerobic and hypoxic cells. These results are consistent with targeting of EF5 to DNA, which was confirmed qualitatively by confocal microscopy.

Animals↗
PubMed1995

Effects of geometric isomerism and ligand substitution in bifunctional dinuclear platinum complexes on binding properties and conformational changes in DNA.

The DNA binding profile of a series of dinuclear platinum complexes [{trans-PtCl-(L)2}2H2N(CH2)nNH2]2+ (L = NH3 or py; 1,1/t,t/NH3 and 1,1/t,t/py, respectively) and [{cis-PtCl-(NH3)2H2N(CH2)nNH2]2+ (1,1/c,c/NH3) was examined to compare the effects of geometrical isomerism and the presence of ligands other than NH3 in the coordination sphere. Steric effects, because of the geometry of the leaving groups cis to the diamine bridge or the presence of planar pyridine ligands, result in diminished binding to calf thymus DNA for these isomers. In contrast, the pyridine derivative shows a distinct binding preference for poly(dG-dC).poly(dG-dC) in comparison to both NH3 isomers. Both NH3 complexes induced the B-->Z transition in poly(dG-dC).poly(dG-dC), but the presence of a pyridine ligand stabilized the B conformation. The bifunctional binding of the NH3 isomers results in unwinding of supercoiled pUC19 plasmid DNA equivalent to cis-DDP, while the unwinding of the pyridine derivative is approximately twice that of the mononuclear trans-[PtCl2(py)2]. DNA-DNA interstrand cross-linking is very efficient for all three agents, but sequencing studies indicated that only the 1,1/t,t/NH3 derivative is capable of forming a (Pt,Pt) intrastrand cross-link to the adjacent guanines of a d(GpG) sequence. The effects on DNA caused by bifunctional binding of dinuclear complexes are compared with those from the mononuclear [PtCl2(NH3)2] isomers. The results are discussed with respect to the antitumor activity of the dinuclear series.

Base Sequence↗
PubMed1995

Characterization of cisplatin-glutathione adducts by liquid chromatography-mass spectrometry. Evidence for their formation in vitro but not in vivo after concomitant administration of cisplatin and glutathione to rats anc cancer patients.

After incubation of equimolar amounts of cisplatin (CDDP) and glutathione (GSH) in phosphate buffer pH 7.4 at 37 degrees C, we detected two CDDP-GSH adducts whose structures, characterized by LC-MS, corresponded to cis-[Pt(NH3)2Cl(SG)] and cis-([Pt(NH3)2Cl]2(mu-SG))+. The latter is a new CDDP-GSH adduct, which was postulated but never structurally characterized so far. Rats and patients were given a 15-min intravenous infusion of CDDP (10 mg/kg to rats and 25 mg/m2 to patients) preceded by a GSH intravenous administration (200 mg/kg to rats as a bolus and 1.5 g/m2 to patients as a 15-min infusion). After the administrations, CDDP-GSH adducts were absent in rat and human plasma ultrafiltrates. The discrepancy between in vitro and in vivo findings can be explained based on pharmacokinetic considerations.

Animals↗
PubMed1995

A novel DNA structure induced by the anticancer bisplatinum compound crosslinked to a GpC site in DNA.

The bifunctional platinum compound, [(trans-PtCI(NH)3)2)2(H2N(CH2)4NH2)]2+, forms a stable adduct with the self-complementary DNA oligomer CATGCATG, with the two platinum atoms coordinated at the N7 positions of the two symmetrical G4 nucleotides. The NMR-derived structure shows that the DNA octamer forms a novel hairpin structure with the platinated G4 residue adopting a syn conformation and the guanine base in the minor groove. Two such hairpins stack end-over-end and are linked together by the butanediamine tether to form a dumbbell structure. Such unusual structural distortion is different from that of the anticancer drug cisplatin-DNA adduct and may provide clues to explain the distinct biological activities of the two compounds.

Antineoplastic Agents↗
PubMed1994

Chemical reactivity and DNA sequence specificity of formally monofunctional and bifunctional bis(platinum) complexes.

The synthesis of the formally monofunctional bis(platinum) complex [(Pt(NH3)3)mu-H2N(CH2)4NH2-(trans-PtCl(NH3)2)]3+ (1,0/t) is reported. The interactions of this species and the formally bifunctional bis(platinum) complex [(trans-PtCl(NH3)2)2H2N(CH2)4NH2]Cl2(1,1/t,t) with DNA were investigated. Comparison was made with the monomeric [PtCl(dien)]Cl, (Pt(DIEN)), and cis-[PtCl2(NH3)2], (cis-DDP). The initial rates of reaction with small self-complementary oligonucleotides 5'-ATATATN4ATATAT-3' (N4 = GCGC and N4 = GGCC) were calculated. For all compounds, the GGCC oligonucleotide reacted faster than the GCGC counterpart. The order of reactivity of the platinum compounds for the GCGC oligonucleotide was 1,1/t,t > 1,0/t > Pt(DIEN) > cis-DDP. The reaction of 1,0/t and 1,1/t,t with poly(dG-dC).poly(dG-dC) was also investigated using circular dichroism (CD) spectroscopy where both compounds were shown to induce a B-->Z conformational change.

Animals↗