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.

• MeSH
• acyklovir analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• DNA účinky léků   MeSH
• fluorescenční spektrometrie MeSH
• molekulární sekvence - údaje MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• sekvence nukleotidů MeSH
• skot MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acyklovir MeSH
• antitumorózní látky MeSH
• diamminechloro(9-(2-hydroxyethoxymethyl)guan-7-yl)platinum(II) MeSH Prohlížeč
• DNA MeSH
• organoplatinové sloučeniny MeSH

• Klíčová slova
• ALK (anaplastic lymphoma kinase), T-cell lymphoma, lymphoma CNS, mycosis fungoides (MF), proteomics,
• Publikační typ
• úvodníky MeSH

In early studies of empirical structure-activity relationships, monodentate Pt(II) complexes were considered to be biologically inactive. Examples of such inactive monodentate Pt(II) compounds are [PtCl(dien)]+ (dien=diethylenetriamine) and [PtCl(NH3)3]+. DNA is considered the major biological target of platinum compounds. Thus, monodentate DNA binding of Pt(II) compounds was previously expected to display insignificant biological effects because it was assumed to affect DNA conformation and downstream cellular processes markedly less than the cross-links of bifunctional Pt(II) complexes. More recently it was shown that some monodentate Pt(II) complexes do exhibit biological effects; the active monodentate Pt(II) complexes commonly feature bulkier amine ligands than the hitherto used dien or NH(3) groups. We were therefore interested in determining whether a simple but marked enhancement of the bulkiness of the dien ligand in monodentate [Pt(NO3)(dien)]+ by multiple methylation of this ligand affects the early phases in which platinum compounds exert their biological activity. More specifically, the goals of this study, performed in cell-free media, were to determine how the modification of DNA duplexes by methylated analogues of [Pt(NO3)(dien)]+ affects their energetics and how the alterations of this biophysical parameter are reflected by the recognition of these duplexes by DNA polymerases and the DNA repair system. We have found that the impact of the methylation of [Pt(NO3)(dien)]+ on the biophysical properties of DNA (thermodynamic, thermal, and conformational properties) and its biochemical processes (DNA polymerization and the repair of DNA adducts) is remarkable. Hence, we conclude that monodentate DNA binding of Pt(II) compounds may considerably affect the biophysical properties of DNA and consequently downstream cellular processes as a result of a large increase in the bulkiness of the nonleaving ligands in this class of metal complex.

• MeSH
• DNA-dependentní DNA-polymerasy chemie   MeSH
• DNA chemie   MeSH
• kalorimetrie MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• metylace MeSH
• molekulární sekvence - údaje MeSH
• molekulární struktura MeSH
• oprava DNA genetika   MeSH
• organoplatinové sloučeniny chemická syntéza   chemie   MeSH
• sekvence nukleotidů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA-dependentní DNA-polymerasy MeSH
• DNA MeSH
• organoplatinové sloučeniny MeSH

In the present work, we measured survival and the platinum on the genome after treatment of repair-proficient or repair-deficient Escherichia coli strains with trans-[PtCl(2)(E-iminoether)(2)] and compared these results with the effects of "classical" cisplatin. We found that toxicity of antitumor trans-[PtCl(2)(E-iminoether)(2)] in repair-deficient trains was much less than that of cisplatin. This markedly reduced toxicity was not a consequence of the reduced uptake or low levels of DNA binding in the bacteria cells but rather appeared to reflect DNA binding mode of this trans-platinum drug different from that of cisplatin.

• MeSH
• antitumorózní látky chemie   metabolismus   farmakologie   MeSH
• cisplatina metabolismus   farmakologie   MeSH
• Escherichia coli účinky léků   genetika   metabolismus   MeSH
• oprava DNA MeSH
• organokovové sloučeniny chemie   metabolismus   farmakologie   MeSH
• organoplatinové sloučeniny chemie   metabolismus   farmakologie   MeSH
• stereoizomerie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• cisplatina MeSH
• dichloroplatinum(E-iminoether)2 MeSH Prohlížeč
• organokovové sloučeniny MeSH
• organoplatinové sloučeniny MeSH

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have high relapse rates following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double-blind randomized phase 3 ECHELON-2 study (#NCT01777152; clinicaltrials.gov) demonstrated improved progression-free survival (PFS) and overall survival with frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP). Herein, we conducted an exploratory subgroups analysis of the impact of consolidative SCT on PFS in patients with previously untreated CD30+ PTCL (ALK- anaplastic large cell lymphoma [ALCL] and non-ALCL) who were in complete response (CR) after frontline treatment with A+CHP or cyclophosphamide, doxorubicin, vincristine, and prednisone. Median PFS follow-up was 47.57 months. The PFS hazard ratio was 0.36, equating to a 64% reduction in the risk of a PFS event in patients who underwent SCT. The median PFS in patients who underwent SCT was not reached, vs 55.66 months in patients who did not undergo SCT. PFS results favored the use of SCT in both ALK- ALCL and non-ALCL subgroups. These data support the consideration of consolidative SCT in patients with CD30+PTCL who achieve CR following treatment with A+CHP.

• MeSH
• anaplastický velkobuněčný lymfom * chemicky indukované   terapie   MeSH
• antigen Ki-1 MeSH
• brentuximab vedotin MeSH
• cyklofosfamid škodlivé účinky   MeSH
• doxorubicin škodlivé účinky   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• prednison škodlivé účinky   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• vinkristin škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antigen Ki-1 MeSH
• brentuximab vedotin MeSH
• cyklofosfamid MeSH
• doxorubicin MeSH
• prednison MeSH
• vinkristin MeSH

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

trans-[PtCl(2)NH(3)(4-Hydroxymethylpyridine)] (trans-PtHMP) is an analogue of clinically ineffective transplatin, which is cytotoxic in the human leukemia cancer cell line. As DNA is a major pharmacological target of antitumor platinum compounds, modifications of DNA by trans-PtHMP and recognition of these modifications by active tumor suppressor protein p53 were studied in cell-free media using the methods of molecular biology and biophysics. Our results demonstrate that the replacement of the NH(3) group in transplatin by the 4-hydroxymethylpyridine ligand affects the character of DNA adducts of parent transplatin. The binding of trans-PtHMP is slower, although equally sequence-specific. This platinum complex also forms on double-stranded DNA stable intrastrand and interstrand cross-links, which distort DNA conformation in a unique way. The most pronounced conformational alterations are associated with a local DNA unwinding, which was considerably higher than those produced by other bifunctional platinum compounds. DNA adducts of trans-PtHMP also reduce the affinity of the p53 protein to its consensus DNA sequence. Thus, downstream effects modulated by recognition and binding of p53 protein to DNA distorted by trans-PtHMP and transplatin are not likely to be the same. It has been suggested that these different effects may contribute to different antitumor effects of these two transplatinum compounds.

• MeSH
• adukty DNA chemie   metabolismus   MeSH
• cirkulární dichroismus MeSH
• DNA účinky léků   metabolismus   MeSH
• genetická transkripce MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• oligonukleotidy MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• pyridiny farmakologie   MeSH
• sekvence nukleotidů MeSH
• skot MeSH
• spektrofotometrie atomová MeSH
• spektrofotometrie ultrafialová MeSH
• thiomočovina chemie   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• DNA MeSH
• nádorový supresorový protein p53 MeSH
• oligonukleotidy MeSH
• organoplatinové sloučeniny MeSH
• pyridiny MeSH
• thiomočovina MeSH
• trans-PtCl(2)NH(3)(4-hydroxymethylpyridine) MeSH Prohlížeč

The new platinum(IV) complex cis,trans,cis-[PtCl(2)(CH(3)COO)(2)-(NH(3))(1-adamantylamine)] [adamplatin(IV)] seems promising for the perspective application in therapy of corresponding tumors. It is therefore of great interest to understand details of mechanisms underlying its biological efficacy. Cellular uptake of the drug, alterations in the target DNA induced by platinum drugs along with processing of platinum-induced damage to DNA and drug inactivation by sulfur-containing compounds belong to major pharmacological factors affecting antitumor effects of platinum compounds. We examined in the present work the significance of these factors in the mechanism of antitumor effects of adamplatin(IV) and compared the results with those of the parallel studies performed with "conventional" cisplatin. The results show that deactivation of adamplatin(IV) by sulfur-containing compounds (such as glutathione or metallothioneins) is likely to play a less significant role in the mechanism of resistance of tumor cells to adamplatin(IV) in contrast to the role of these reactions in the effects of cisplatin. Moreover, the treatment of tumor cells with adamplatin(IV) does not result in DNA modifications that would be markedly different from those produced by cisplatin. In contrast, the effects of other factors, such as enhanced accumulation of the drug in cells, strong inhibition of DNA polymerization by these adducts, lowered DNA repair, and DNA-protein cross-linking are different from the effects of these factors in the mechanism underlying activity of cisplatin. Hence, the differences between effects of adamplatin(IV) and cisplatin observed in the present work on molecular level may help understand the unique activity of adamplatin(IV).

• MeSH
• adamantan analogy a deriváty   terapeutické užití   MeSH
• adukty DNA účinky léků   MeSH
• antitumorózní látky terapeutické užití   MeSH
• bezbuněčný systém MeSH
• DNA řízené RNA-polymerasy metabolismus   MeSH
• DNA biosyntéza   MeSH
• HeLa buňky MeSH
• HIV-1 enzymologie   MeSH
• krysa rodu Rattus MeSH
• kyselina askorbová metabolismus   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• oprava DNA genetika   MeSH
• organoplatinové sloučeniny terapeutické užití   MeSH
• platina metabolismus   MeSH
• plazmidy genetika   MeSH
• proteiny s vysokou pohyblivostí metabolismus   MeSH
• reagencia zkříženě vázaná MeSH
• reverzní transkriptasa metabolismus   MeSH
• sekvence nukleotidů MeSH
• sloučeniny síry metabolismus   MeSH
• virové proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• (PtCl(2)(CH(3)COO)(2)-(NH(3))(1-adamantylamine)) MeSH Prohlížeč
• adamantan MeSH
• adukty DNA MeSH
• antitumorózní látky MeSH
• bacteriophage T7 RNA polymerase MeSH Prohlížeč
• DNA řízené RNA-polymerasy MeSH
• DNA MeSH
• kyselina askorbová MeSH
• organoplatinové sloučeniny MeSH
• platina MeSH
• proteiny s vysokou pohyblivostí MeSH
• reagencia zkříženě vázaná MeSH
• reverzní transkriptasa MeSH
• sloučeniny síry MeSH
• virové proteiny MeSH

BACKGROUND: Nodal peripheral T-cell lymphomas (PTCLs) are infrequent subtypes of non-Hodgkin's lymphomas. The WHO classification recognizes three subgroups of nodal PTCL: peripheral T-cell lymphoma not otherwise specified (PTCL, NOS), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic lymphoma (AIL). The clinical course is aggressive and despite multiagent chemotherapy, the median survival is about 2 years. Optimal first-line chemotherapy is not established and the role of high-dose therapy with autologous stem cell support is still controversial. AIM: To analyze the long-term outcome of PTCL patients treated with intensive first-line chemotherapy with highdose therapy and autologous transplant consolidation. METHOD: Sequential chemotherapy protocol consisting of 3 cycles of CHOEP-21-like regimen (PACEBO), 1 cycle of an ifosfamide and methotrexate-based regimen (IVAM) and a priming regimen with high-dose cytosine arabinoside (HAM). Consolidation was provided with myeloablative conditioning (BEAM 200) and autologous stem cell support. Eighty-four patients with aggressive high-risk lymphoma were treated with the sequential protocol from 2000 to 2007 in our institution. Here we report our experience with 18 patients with nodal PTCL (10 PTCL, NOS; 3 ALCL, ALKnegative; 2 ALCL, ALK-positive; 2 ALCL, unknown ALK status; 1 AIL). RESULTS: Eleven (61 %) patients achieved complete remission, 3 (17 %) partial remission and 4 (22 %) patients failed the procedure. The overall response rate was 77.8 %. After a median follow-up of 25.7 months, nine patients relapsed or progressed (6 PTCL, NOS; 2 ALCL ALK-positive; 1 ALCL ALK-negative; median 14.1 months) and four patients died (lymphoma progression). The relapse was treated with allogeneic stem transplantation in one patient. The 2-year progression-free survival (PFS) was 52 % (95 % CI, 0.27 to 0.76); the 2-year overall survival rate reached 71 % (95 % CI, 0.47 to 0.95). CONCLUSION: Our results show that intensive first-line chemotherapy with high-dose therapy and autologous transplant consolidation offers a chance for long-term survival in patients with chemosensitive PTCL.

• MeSH
• dospělí MeSH
• homologní transplantace MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• periferní T-buněčný lymfom mortalita   terapie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Pediatric-type follicular (PTFL), marginal zone (MZL), and peripheral T-cell lymphoma (PTCL) account each for <2% of childhood non-Hodgkin lymphoma. We present clinical and histopathological features of PTFL, MZL, and few subtypes of PTCL and provide treatment recommendations. For localized PTFL and MZL, watchful waiting after complete resection is the therapy of choice. For PTCL, therapy is subtype-dependent and ranges from a block-like anaplastic large cell lymphoma (ALCL)-derived and, alternatively, leukemia-derived therapy in PTCL not otherwise specified and subcutaneous panniculitis-like T-cell lymphoma to a block-like mature B-NHL-derived or, preferentially, ALCL-derived treatment followed by hematopoietic stem cell transplantation in first remission in hepatosplenic and angioimmunoblastic T-cell lymphoma.

• Klíčová slova
• follicular lymphoma, marginal zone lymphoma, non-Hodgkin lymphoma, peripheral T-cell lymphoma, rare,
• MeSH
• alografty MeSH
• dítě MeSH
• folikulární lymfom * diagnóza   terapie   MeSH
• kojenec MeSH
• lidé MeSH
• lymfom z B-buněk marginální zóny * diagnóza   terapie   MeSH
• mladiství MeSH
• periferní T-buněčný lymfom * diagnóza   terapie   MeSH
• předškolní dítě MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH