DNA-dependent DNA and RNA polymerases are important modulators of biological functions such as replication, transcription, recombination, or repair. In this work performed in cell-free media, we studied the ability of selected DNA polymerases to overcome a monofunctional adduct of the cytotoxic/antitumor platinum-acridinylthiourea conjugate [PtCl(en)(L)](NO3)2 (en = ethane-1,2-diamine, L = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) (ACR) in its favored 5'-CG sequence. We focused on how a single site-specific ACR adduct with intercalation potency affects the processivity and fidelity of DNA-dependent DNA polymerases involved in translesion synthesis (TLS) and repair. The ability of the G(N7) hybrid ACR adduct formed in the 5'-TCGT sequence of a 24-mer DNA template to inhibit the synthesis of a complementary DNA strand by the exonuclease-deficient Klenow fragment of DNA polymerase I (KFexo-) and human polymerases eta, kappa, and iota was supplemented by thermodynamic analysis of the polymerization process. Thermodynamic parameters of a simulated translesion synthesis across the ACR adduct were obtained by using microscale thermophoresis (MST). Our results show a strong inhibitory effect of an ACR adduct on enzymatic TLS: there was only small synthesis of a full-length product (less than 10%) except polymerase eta (~20%). Polymerase eta was able to most efficiently bypass the ACR hybrid adduct. Incorporation of a correct dCMP opposite the modified G residue is preferred by all the four polymerases tested. On the other hand, the frequency of misinsertions increased. The relative efficiency of misinsertions is higher than that of matched cytidine monophosphate but still lower than for the nonmodified control duplex. Thermodynamic inspection of the simulated TLS revealed a significant stabilization of successively extended primer/template duplexes containing an ACR adduct. Moreover, no significant decrease of dissociation enthalpy change behind the position of the modification can contribute to the enzymatic TLS observed with the DNA-dependent, repair-involved polymerases. This TLS could lead to a higher tolerance of cancer cells to the ACR conjugate compared to its enhanced analog, where thiourea is replaced by an amidine group: [PtCl(en)(L)](NO3)2 (complex AMD, en = ethane-1,2-diamine, L = N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine).

• Klíčová slova
• DNA polymerases, antitumor, cytotoxic, drug resistance, lesion bypass, metal–intercalator, microscale thermophoresis, platinum–acridine, thermodynamic, translesion synthesis,
• MeSH
• adukty DNA chemie   MeSH
• DNA-dependentní DNA-polymerasy metabolismus   MeSH
• interkalátory chemie   MeSH
• lidé MeSH
• močovina analogy a deriváty   chemie   MeSH
• oprava DNA * MeSH
• organoplatinové sloučeniny chemie   MeSH
• poškození DNA * MeSH
• replikace DNA MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1-(2-(acridin-9-ylamino)ethyl)-1,3-dimethylthiourea MeSH Prohlížeč
• adukty DNA MeSH
• DNA-dependentní DNA-polymerasy MeSH
• interkalátory MeSH
• močovina MeSH
• organoplatinové sloučeniny MeSH

Translesion synthesis (TLS) through DNA adducts of antitumor platinum complexes has been an interesting aspect of DNA synthesis in cells treated with these metal-based drugs because of its correlation to drug sensitivity. We utilized model systems employing a DNA lesion derived from a site-specific monofunctional adduct formed by antitumor [PtCl(en)(L)](NO3)2 (complex AMD, en = ethane-1,2-diamine, L = N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine) at a unique G residue. The catalytic efficiency of TLS DNA polymerases, which differ in their processivity and fidelity for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the adduct of AMD, was investigated. For a deeper understanding of the factors that control the bypass of the site-specific adducts of AMD catalyzed by DNA polymerases, we also used microscale thermophoresis (MST) to measure the thermodynamic changes associated with TLS across a single, site-specific adduct formed in DNA by AMD. The relative catalytic efficiency of the investigated DNA polymerases for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the AMD adduct, was reduced. Nevertheless, incorporation of the correct C opposite the G modified by AMD of the template strand was promoted by an increasing thermodynamic stability of the resulting duplex. The reduced relative efficiency of the investigated DNA polymerases may be a consequence of the DNA intercalation of the acridine moiety of AMD and the size of the adduct. The products of the bypass of this monofunctional lesion produced by AMD and DNA polymerases also resulted from the misincorporation of dNTPs opposite the platinated G residues. The MST analysis suggested that thermodynamic factors may contribute to the forces that governed enhanced incorporation of the incorrect dNTPs by DNA polymerases.

• Klíčová slova
• DNA polymerases, antitumor, microscale thermophoresis, platinum-acridine, translesion DNA synthesis,
• MeSH
• adukty DNA chemie   genetika   metabolismus   MeSH
• akridiny chemie   farmakologie   MeSH
• biokatalýza MeSH
• DNA-dependentní DNA-polymerasy metabolismus   MeSH
• DNA biosyntéza   MeSH
• guanin metabolismus   MeSH
• katalýza MeSH
• nukleotidy genetika   metabolismus   MeSH
• oprava DNA MeSH
• replikace DNA MeSH
• sloučeniny platiny chemie   farmakologie   MeSH
• tepelná difuze MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adukty DNA MeSH
• akridiny MeSH
• DNA-dependentní DNA-polymerasy MeSH
• DNA MeSH
• guanin MeSH
• nukleotidy MeSH
• sloučeniny platiny MeSH

The moderate-to-high in vitro cytotoxicity against ovarian A2780 (IC50 = 4.7-14.4 μM), prostate LNCaP (IC50 = 18.7-30.8 μM) and prostate PC-3 (IC50 = 17.6-42.3 μM) human cancer cell lines of the platinum(II) cyclobutane-1,1'-dicarboxylato complexes [Pt(cbdc)(naza)2] (1-6; cbdc = cyclobutane-1,1'-dicarboxylate(2-); naza = halogeno-substituted 7-azaindoles), derived from the anticancer metallodrug carboplatin, are reported. The complexes containing the chloro- and bromo-substituted 7-azaindoles (1, 2, and 4-6) showed a significantly higher (p < 0.05) cytotoxicity against A2780 cell line as compared to cisplatin used as a reference drug. Addition of the non-toxic concentration (5.0 μM) of L-buthionine sulfoximine (L-BSO, an effective inhibitor of γ-glutamylcysteine synthase) markedly increases the in vitro cytotoxicity of the selected complex 3 against A2780 cancer cell line by a factor of about 4.4. The cytotoxicity against A2780 and LNCaP cells, as well as the DNA platination, were effectively enhanced by UVA light irradiation (λmax = 365 nm) of the complexes, with the highest phototoxicity determined for compound 3, resulting in a 4-fold decline in the A2780 cells viability from 25.1% to 6.1%. The 1H NMR and ESI-MS experiments suggested that the complexes did not interact with glutathione as well as their ability to interact with guanosine monophosphate. The studies also confirmed UVA light induced the formation of the cis [Pt(H2O)2(cbdc`)(naza)] intermediate, where cbdc` represents monodentate-coordinated cbdc ligand, which is thought to be responsible for the enhanced cytotoxicity. This is further supported by the results of transcription mapping experiments showing that the studied complexes preferentially form the bifunctional adducts with DNA under UVA irradiation, in contrast to the formation of the less effective monofunctional adducts in dark.

• MeSH
• adukty DNA chemie   genetika   MeSH
• buthionin sulfoximin farmakologie   MeSH
• dvouřetězcové zlomy DNA účinky léků   účinky záření   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• indoly chemie   farmakologie   MeSH
• karboplatina chemie   farmakologie   MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• nádory genetika   patologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• protonová magnetická rezonanční spektroskopie MeSH
• synergismus léků MeSH
• ultrafialové záření * MeSH
• viabilita buněk účinky léků   genetika   účinky záření   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-azaindole dimer MeSH Prohlížeč
• adukty DNA MeSH
• buthionin sulfoximin MeSH
• indoly MeSH
• karboplatina MeSH
• protinádorové látky MeSH

When antitumor platinum drugs react with DNA they form various types of intrastrand and interstrand cross-links (CLs). One class of new antitumor platinum compounds comprises bifunctional Pt(II) compounds based on the dinuclear or trinuclear geometry of leaving ligands. It has been shown that the DNA-binding modes of dinuclear or trinuclear bifunctional Pt(II) agents are distinct from those of mononuclear cisplatin, forming markedly more intramolecular interstrand CLs. However, at least two types of DNA interstrand cross-linking by bifunctional Pt(II) complexes can be envisaged, depending on whether the platinum complex coordinates to the bases in one DNA molecule (intramolecular interstrand CLs) or in two different DNA duplexes (interduplex CLs). We hypothesized that at least some antitumor bifunctional poly(di/tri)nuclear complexes could fulfill the requirements placed on interduplex DNA cross-linkers. To test this hypothesis we studied the interduplex cross-linking capability of a representative of antitumor polynuclear agents, namely, dinuclear Pt(II) complex [{trans-PtCl(NH(3))(2)}(2)-μ-{trans-(H(2)N(CH(2))(6)NH(2)(CH(2))(2)NH(2)(CH(2))(6)NH(2))}](4+) (BBR3535). The investigations were conducted under molecular crowding conditions mimicking environmental conditions in the cellular nucleus, namely, in medium containing ethanol, which is a commonly used crowding agent. We found with the aid of native agarose gel electrophoresis that the DNA interduplex cross-linking efficiency of BBR3535 under molecular crowding conditions was remarkable: the frequency of these CLs was 54%. In contrast, the interduplex cross-linking efficiency of mononuclear cisplatin or transplatin was markedly lower (approximately 40-fold or 18-fold, respectively). We suggest that the production of interduplex CLs in addition to other DNA intramolecular adducts may provide polynuclear Pt(II) compounds with a wider spectrum of cytotoxicity.

• MeSH
• adukty DNA chemie   metabolismus   MeSH
• DNA chemie   metabolismus   MeSH
• interkalátory chemie   farmakologie   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• organoplatinové sloučeniny chemie   farmakologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reagencia zkříženě vázaná chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• DNA MeSH
• interkalátory MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH

The global modification of mammalian and plasmid DNAs by the novel platinum compounds cis-[PtCl(2)(isopropylamine)(1-methylimidazole)] and trans-[PtCl(2)(isopropylamine)(1-methylimidazole)] and the reactivity of these compounds with reduced glutathione (GSH) were investigated in cell-free media using various biochemical and biophysical methods. Earlier cytotoxicity studies had revealed that the replacement of the NH(3) groups in cisplatin by the azole and isopropylamine ligands lowers the activity of cisplatin in both sensitive and resistant cell lines. The results of the present work show that this replacement does not considerably affect the DNA modifications by this drug, recognition of these modifications by HMGB1 protein, their repair, and reactivity of the platinum complex with GSH. These results were interpreted to mean that the reduced activity of this analog of cisplatin in tumor cell lines is due to factors that do not operate at the level of the target DNA. In contrast, earlier studies had shown that the replacement of the NH(3) groups in the clinically ineffective trans isomer (transplatin) by the azole and isopropylamine ligands results in a radical enhancement of its activity in tumor cell lines. Importantly, this replacement also markedly alters the DNA binding mode of transplatin, which is distinctly different from that of cisplatin, but does not affect reactivity with GSH. Hence, the results of the present work are consistent with the view and support the hypothesis systematically tested by us and others that platinum drugs that bind to DNA in a fundamentally different manner from that of conventional cisplatin may have altered pharmacological properties.

• MeSH
• bezbuněčný systém MeSH
• cirkulární dichroismus MeSH
• DNA chemie   účinky léků   MeSH
• glutathion chemie   účinky léků   MeSH
• kultivační média chemie   MeSH
• lidé MeSH
• organoplatinové sloučeniny chemie   farmakologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• spektrofotometrie ultrafialová MeSH
• stereoizomerie MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dichloro(isopropylamine)(1-methylimidazole)diplatinum(II) MeSH Prohlížeč
• DNA MeSH
• glutathion MeSH
• kultivační média MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH

DNA-protein cross-links are formed by various DNA-damaging agents including antitumor platinum drugs. The natures of these ternary DNA-Pt-protein complexes (DPCLs) can be inferred, yet much remains to be learned about their structures and mechanisms of formation. We investigated the origin of these DPCLs and their cellular processing on molecular level using gel electrophoresis shift assay. We show that in cell-free media cisplatin [cis-diamminedichloridoplatinum(II)] forms DPCLs more effectively than ineffective transplatin [trans-diamminedichloridoplatinum(II)]. Mechanisms of transformation of individual types of plain DNA adducts of the platinum complexes into the DPCLs in the presence of several DNA-binding proteins have been also investigated. The DPCLs are formed by the transformation of DNA monofunctional and intrastrand cross-links of cisplatin. In contrast, interstrand cross-links of cisplatin and monofunctional adducts of transplatin are stable in presence of the proteins. The DPCLs formed by cisplatin inhibit DNA polymerization or removal of these ternary lesions from DNA by nucleotide excision repair system more effectively than plain DNA intrastrand or monofunctional adducts. Thus, the bulky DNA-protein cross-links formed by cisplatin represent a more distinct and persisting structural motif recognized by the components of downstream cellular systems processing DNA damage considerably differently than the plain DNA adducts of this metallodrug.

• MeSH
• adukty DNA chemie   MeSH
• cisplatina chemie   toxicita   MeSH
• DNA vazebné proteiny účinky léků   MeSH
• DNA biosyntéza   účinky léků   MeSH
• oprava DNA MeSH
• protinádorové látky chemie   toxicita   MeSH
• reagencia zkříženě vázaná chemie   toxicita   MeSH
• retardační test MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• cisplatin-DNA adduct MeSH Prohlížeč
• cisplatina MeSH
• DNA vazebné proteiny MeSH
• DNA MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH
• transplatin MeSH Prohlížeč

Replacement of one ammine in clinically ineffective trans-[PtCl2(NH3)2] (transplatin) by a planar N-heterocycle, thiazole, results in significantly enhanced cytotoxicity. Unlike 'classical' cisplatin {cis-[PtCl2(NH3)2]} or transplatin, modification of DNA by this prototypical cytotoxic transplatinum complex trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) leads to monofunctional and bifunctional intra or interstrand adducts in roughly equal proportions. DNA fragments containing site-specific bifunctional DNA adducts of trans-PtTz were prepared. The structural distortions induced in DNA by these adducts and their consequences for high-mobility group protein recognition, DNA polymerization and nucleotide excision repair were assessed in cell-free media by biochemical methods. Whereas monofunctional adducts of trans-PtTz behave similar to the major intrastrand adduct of cisplatin [J. Kasparkova, O. Novakova, N. Farrell and V. Brabec (2003) Biochemistry, 42, 792-800], bifunctional cross-links behave distinctly differently. The results suggest that the multiple DNA lesions available to trans-planaramine complexes may all contribute substantially to their cytotoxicity so that the overall drug cytotoxicity could be the sum of the contributions of each of these adducts. However, acquisition of drug resistance could be a relatively rare event, since it would have to entail resistance to or tolerance of multiple, structurally dissimilar DNA lesions.

• MeSH
• adukty DNA chemie   metabolismus   MeSH
• cisplatina chemie   toxicita   MeSH
• DNA biosyntéza   MeSH
• konformace nukleové kyseliny MeSH
• oprava DNA MeSH
• organoplatinové sloučeniny chemie   toxicita   MeSH
• proteiny s vysokou pohyblivostí metabolismus   MeSH
• protinádorové látky chemie   toxicita   MeSH
• reagencia zkříženě vázaná chemie   toxicita   MeSH
• thiazoly chemie   toxicita   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adukty DNA MeSH
• cisplatina MeSH
• DNA MeSH
• organoplatinové sloučeniny MeSH
• proteiny s vysokou pohyblivostí MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH
• thiazoly MeSH
• trans-(PtCl2(NH3)(thiazole)) MeSH Prohlížeč
• transplatin MeSH Prohlížeč

The structure-pharmacological activity relationships generally accepted for antitumor platinum compounds stressed the necessity for the cis-[PtX(2)(amine)(2)] structure while the trans-[PtX(2)(amine)(2)] structure was considered inactive. However, more recently, several trans-platinum complexes have been identified which are potently toxic, antitumor-active and demonstrate activity distinct from that of conventional cisplatin (cis-[PtCl(2)(NH(3))(2)]). We have shown in the previous report that the replacement of ammine ligands by iminoether in transplatin (trans-[PtCl(2)(NH(3))(2)]) results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant antitumor activity, including activity in cisplatin-resistant tumor cells. In addition, we have also shown previously that this new trans compound (trans-[PtCl(2)(E-iminoether)(2)]) forms mainly monofunctional adducts at guanine residues on DNA, which is generally accepted to be the cellular target of platinum drugs. In order to shed light on the mechanism underlying the antitumor activity of trans-[PtCl(2)(E-iminoether)(2)] we examined oligodeoxyribonucleotide duplexes containing a single, site-specific, monofunctional adduct of this transplatin analog by the methods of molecular biophysics. The results indicate that major monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] locally distort DNA, bend the DNA axis by 21 degrees toward the minor groove, are not recognized by HMGB1 proteins and are readily removed from DNA by nucleotide excision repair (NER). In addition, the monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA polymerases in vitro and to inhibit removal of this adduct from DNA by NER. It is suggested that DNA-protein ternary cross-links produced by trans-[PtCl(2)(E-iminoether)(2)] could persist considerably longer than the non-cross-linked monofunctional adducts, which would potentiate toxicity of this antitumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl(2)(E-iminoether)(2)] represents a quite new class of platinum antitumor drugs in which activation of trans geometry is associated with an increased efficiency to form DNA-protein ternary cross-links thereby acting by a different mechanism from 'classical' cisplatin and its analogs.

• MeSH
• adukty DNA chemie   metabolismus   MeSH
• CHO buňky MeSH
• cisplatina analogy a deriváty   chemie   farmakologie   MeSH
• DNA-dependentní DNA-polymerasy metabolismus   MeSH
• DNA chemie   účinky léků   metabolismus   MeSH
• domény HMG-Box MeSH
• HeLa buňky MeSH
• konformace nukleové kyseliny účinky léků   MeSH
• křečci praví MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• makromolekulární látky MeSH
• oligonukleotidy chemie   metabolismus   MeSH
• protein HMGB1 chemie   metabolismus   MeSH
• reagencia zkříženě vázaná chemie   farmakologie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• cisplatina MeSH
• DNA-dependentní DNA-polymerasy MeSH
• DNA MeSH
• makromolekulární látky MeSH
• oligonukleotidy MeSH
• protein HMGB1 MeSH
• reagencia zkříženě vázaná MeSH

Platinum(II) diam(m)ine complexes such as cisplatin are effective anticancer drugs but have accompanying side effects. We are exploring the design of platinum complexes with low toxicity that could be photoactivated selectively at the target site. We show here that the Pt(IV) azide complex cis, trans-[Pt(en)(N(3))(2)(OH)(2)] is unreactive towards DNA until irradiated with visible light. Transcription mapping studies of a 212-bp fragment of pSP73KB plasmid DNA treated with cis, trans-[Pt(en)(N(3))(2)(OH)(2)] and irradiated with visible light showed that the platination sites were similar to those observed for cisplatin, and were mainly in GG sequences. HPLC analysis of enzymatic digests of an irradiated sample of a 40-bp DNA duplex treated with the same complex also revealed preferential formation of GG cross-links. Since such DNA lesions are thought to be responsible for the induction of apoptosis in cancer cells by platinum drugs, the use of unreactive photoactivatable platinum pro-drugs may become an effective strategy for the design of a new generation of platinum anticancer complexes.

• MeSH
• adukty DNA chemická syntéza   izolace a purifikace   MeSH
• azidy chemie   MeSH
• cisplatina chemie   MeSH
• DNA chemie   MeSH
• fotochemie MeSH
• fotochemoterapie MeSH
• genetická transkripce MeSH
• guanin chemie   MeSH
• protinádorové látky chemie   MeSH
• sekvence nukleotidů MeSH
• sloučeniny platiny chemie   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• azidy MeSH
• cisplatina MeSH
• DNA MeSH
• guanin MeSH
• protinádorové látky MeSH
• sloučeniny platiny MeSH

Antitumor cisplatin [cis-diamminedichloroplatinum(II)] forms on DNA predominantly intrastrand cross-links between neighboring purine residues. Several discoveries suggested that the toxicity of cisplatin originated from these lesions. The formation of 1,2-GG intrastrand cross-link of cisplatin leads to marked conformational alterations in DNA including a directional, rigid bend toward the major groove and local unwinding. These altered structures attract various cellular proteins. This phenomenon has been postulated to mediate antitumor properties of cisplatin. Importantly, the binding affinity of several proteins that specifically recognize 1,2-GG intrastrand cross-link to platinated DNA is modulated by the nature of the base pairs that immediately flank the platinated d(GpG) site. However, the influence of sequence context on DNA bending and unwinding due to the formation of the 1,2-GG intrastrand cross-link has not been extensively investigated. In the present study we have employed electrophoretic retardation (phasing) assay to analyze bending and unwinding induced by the single, site-specific 1,2-GG intrastrand cross-link immediately flanked by various bases formed by cisplatin in nine oligodeoxyribonucleotide duplexes. The results indicate that bending and unwinding of DNA as a consequence of the formation of the major adduct of cisplatin is, in the first approximation, independent of the base pairs flanking the platinated d(GpG) site.

• MeSH
• adukty DNA * MeSH
• cisplatina chemie   farmakologie   MeSH
• DNA chemie   genetika   MeSH
• guanosin chemie   MeSH
• konformace nukleové kyseliny účinky léků   MeSH
• oligonukleotidy chemie   genetika   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• sekvence nukleotidů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA * MeSH
• cisplatina MeSH
• DNA MeSH
• guanosin MeSH
• oligonukleotidy MeSH
• protinádorové látky MeSH