The purine derivative fludarabine is part of frontline therapy for chronic lymphocytic leukaemia (CLL). It has shown positive effects on solid tumours such as melanoma, breast, and colon carcinoma in clinical phase I studies. As the treatment of CLL cells with combinations of fludarabine and metal complexes of antitumoural natural products, e.g., illudin M ferrocene, has led to synergistically enhanced apoptosis, in this research study different complexes of fludarabine itself. Four complexes bearing a trans-[Br(PPh3)2]Pt/Pd fragment attached to atom C-8 via formal η1-sigma or η2-carbene bonds were synthesised in two or three steps without protecting polar groups on the arabinose or adenine. The platinum complexes were more cytotoxic than their palladium analogues, with low single-digit micromolar IC50 values against cells of various solid tumour entities, including cisplatin-resistant ones and certain B-cell lymphoma and CLL, presumably due to the ten-fold higher cellular uptake of the platinum complexes. However, the palladium complexes interacted more readily with isolated Calf thymus DNA. Interestingly, the platinum complexes showed vastly greater selectivity for cancer over non-malignant cells when compared with fludarabine.

• Klíčová slova
• CLL, anticancer drugs, fludarabine, lymphoma, metal–drug synergy, platinum complexes,
• MeSH
• antimetabolity terapeutické užití   MeSH
• chronická lymfatická leukemie * farmakoterapie   MeSH
• imunosupresiva terapeutické užití   MeSH
• lidé MeSH
• palladium chemie   MeSH
• platina chemie   MeSH
• protinádorové látky * chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antimetabolity MeSH
• fludarabine MeSH Prohlížeč
• imunosupresiva MeSH
• palladium MeSH
• platina MeSH
• protinádorové látky * MeSH

Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

• Klíčová slova
• cancer, drug, inhibitor, transcription, translation,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Mantle cell lymphoma (MCL) is a chronically relapsing aggressive type of B-cell non-Hodgkin lymphoma considered incurable by currently used treatment approaches. Fludarabine is a purine analog clinically still widely used in the therapy of relapsed MCL. Molecular mechanisms of fludarabine resistance have not, however, been studied in the setting of MCL so far. We therefore derived fludarabine-resistant MCL cells (Mino/FR) and performed their detailed functional and proteomic characterization compared to the original fludarabine sensitive cells (Mino). We demonstrated that Mino/FR were highly cross-resistant to other antinucleosides (cytarabine, cladribine, gemcitabine) and to an inhibitor of Bruton tyrosine kinase (BTK) ibrutinib. Sensitivity to other types of anti-lymphoma agents was altered only mildly (methotrexate, doxorubicin, bortezomib) or remained unaffacted (cisplatin, bendamustine). The detailed proteomic analysis of Mino/FR compared to Mino cells unveiled over 300 differentially expressed proteins. Mino/FR were characterized by the marked downregulation of deoxycytidine kinase (dCK) and BTK (thus explaining the observed crossresistance to antinucleosides and ibrutinib), but also by the upregulation of several enzymes of de novo nucleotide synthesis, as well as the up-regulation of the numerous proteins of DNA repair and replication. The significant upregulation of the key antiapoptotic protein Bcl-2 in Mino/FR cells was associated with the markedly increased sensitivity of the fludarabine-resistant MCL cells to Bcl-2-specific inhibitor ABT199 compared to fludarabine-sensitive cells. Our data thus demonstrate that a detailed molecular analysis of drug-resistant tumor cells can indeed open a way to personalized therapy of resistant malignancies.

• MeSH
• chemorezistence * MeSH
• chromatografie kapalinová metody   MeSH
• izotopové značení metody   MeSH
• lidé MeSH
• lymfom z plášťových buněk farmakoterapie   metabolismus   MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buňky kultivované MeSH
• proteomika metody   MeSH
• protinádorové látky farmakologie   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• vidarabin analogy a deriváty   farmakologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fludarabine MeSH Prohlížeč
• nádorové biomarkery MeSH
• protinádorové látky MeSH
• vidarabin MeSH

ATM abnormalities are frequent in chronic lymphocytic leukemia and represent an important prognostic factor. Sole 11q deletion does not result in ATM inactivation by contrast to biallelic defects involving mutations. Therefore, the analysis of ATM mutations and their functional impact is crucial. In this study, we analyzed ATM mutations in predominantly high-risk patients using: i) resequencing microarray and direct sequencing; ii) Western blot for total ATM level; iii) functional test based on p21 gene induction after parallel treatment of leukemic cells with fludarabine and doxorubicin. ATM dysfunction leads to impaired p21 induction after doxorubicin exposure. We detected ATM mutation in 16% (22 of 140) of patients, and all mutated samples manifested demonstrable ATM defect (impaired p21 upregulation after doxorubicin and/or null protein level). Loss of ATM function in mutated samples was also evidenced through defective p53 pathway activation after ionizing radiation exposure. ATM mutation frequency was 34% in patients with 11q deletion, 4% in the TP53-defected group, and 8% in wild-type patients. Our functional test, convenient for routine use, showed high sensitivity (80%) and specificity (97%) for ATM mutations prediction. Only cells with ATM mutation, but not those with sole 11q deletion, were resistant to doxorubicin. As far as fludarabine is concerned, this difference was not observed. Interestingly, patients from both these groups experienced nearly identical time to first treatment. In conclusion, ATM mutations either alone or in combination with 11q deletion uniformly led to demonstrable ATM dysfunction in patients with chronic lymphocytic leukemia and mutation presence can be predicted by the functional test using doxorubicin.

• MeSH
• ATM protein antagonisté a inhibitory   genetika   fyziologie   MeSH
• chromozomální delece MeSH
• chronická lymfatická leukemie diagnóza   genetika   patologie   MeSH
• dospělí MeSH
• doxorubicin farmakologie   MeSH
• kohortové studie MeSH
• leukocyty mononukleární účinky léků   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 11 genetika   MeSH
• mutace genetika   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• viabilita buněk účinky léků   fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• doxorubicin MeSH