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Hairy cell leukemia (HCL) represents 2% of all leukemia cases, with men aged above 55 years being the most affected. The most common symptoms of this type of leukemia include splenomegaly, monocytopenia, and neutropenia. In the basic blood count examination, leukopenia with monocytopenia and granulocytopenia, as well as aplastic anemia and/or thrombocytopenia occur. The mutation of β-rapidly accelerated fibrosarcoma (BRAF) proto-oncogene, which can be found in nearly 100% of patients, is an important feature of HCL. Immunophenotypic analysis of the HCL cells reveals high expression of B-lineage antigens, including CD19, CD20, and CD22. Additionally, CD11c, CD25, CD103, and CD123 belong to specific markers of HCL. Lactate dehydrogenase activity and β-2-microglobulin concentration are also important in the patient's assessment. The differential diagnosis between HCL, hairy cell leukemia variant (HCL-V) and splenic marginal zone lymphoma (SMZL) is of first importance. Currently, the main treatment for HCL involves the use of purine analogues, excluding pregnant women, individuals with severe infections, and those with relapsing HCL. [ABSTRACT FROM AUTHOR]

Patients with lymphoid malignancies are at increased risk of death or prolonged infection due to COVID-19. Data on the influence of different antineoplastic treatment modalities on outcomes are conflicting. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is unclear whether this risk is affected by the choice of the antibody (rituximab vs. obinutuzumab). To elucidate the role of antineoplastic therapy on COVID-19 outcomes, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID-19 between October 2020 and April 2021. A total of 314 patients were identified, 75 untreated, 61 off treatment and 178 on treatment. The mortality rate in untreated and off-treatment patients was 15% and 16%; 9% and 10% had prolonged infection. In the on-treatment group, 3% were still prolonged positive at time of data collection, 62% recovered and 35% died; 42% had prolonged infection. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older patients (p = 0.0078) and those treated with purine analogues (p = 0.012). Prolonged COVID-19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (p = 0.012), especially obinutuzumab, and purine analogues (p = 0.012). Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. These data suggest that increased age and use of purine analogues are main risk factors for increased mortality of COVID-19 in patients with lymphoid malignancies. Obinutuzumab further increases the risk of prolonged disease, but not of death, in comparison to rituximab. Epidemiological considerations should be taken into account when choosing the appropriate antineoplastic therapy for patients with lymphoid malignancies. [ABSTRACT FROM AUTHOR]

Purine analogues are important therapeutic tools due to their affinity to enzymes or receptors that are involved in critical biological processes. In this study, new 1,4,6-trisubstituted pyrazolo[3,4-b]pyridines were designed and synthesized, and their cytotoxic potential was been studied. The new derivatives were prepared through suitable arylhydrazines, and upon successive conversion first to aminopyrazoles, they were converted then to 1,6-disubstituted pyrazolo[3,4-b]pyridine-4-ones; this served as the starting point for the synthesis of the target compounds. The cytotoxic activity of the derivatives was evaluated against several human and murine cancer cell lines. Substantial structure activity relationships (SARs) could be extracted, mainly concerning the 4-alkylaminoethyl ethers, which showed potent in vitro antiproliferative activity in the low μM level (0.75–4.15 μΜ) without affecting the proliferation of normal cells. The most potent analogues underwent in vivo evaluation and were found to inhibit tumor growth in vivo in an orthotopic breast cancer mouse model. The novel compounds exhibited no systemic toxicity; they affected only the implanted tumors and did not interfere with the immune system of the animals. Our results revealed a very potent novel compound which could be an ideal lead for the discovery of promising anti-tumor agents, and could also be further explored for combination treatments with immunotherapeutic drugs. [ABSTRACT FROM AUTHOR]

Patients with lymphoid malignancies are at increased risk of death or prolonged infection due to COVID-19. Data on the influence of different antineoplastic treatment modalities on outcomes are conflicting. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is unclear whether this risk is affected by the choice of the antibody (rituximab vs. obinutuzumab). To elucidate the role of antineoplastic therapy on COVID-19 outcomes, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID-19 between October 2020 and April 2021. A total of 314 patients were identified, 75 untreated, 61 off treatment and 178 on treatment. The mortality rate in untreated and off-treatment patients was 15% and 16%; 9% and 10% had prolonged infection. In the on-treatment group, 3% were still prolonged positive at time of data collection, 62% recovered and 35% died; 42% had prolonged infection. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older patients (p = 0.0078) and those treated with purine analogues (p = 0.012). Prolonged COVID-19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (p = 0.012), especially obinutuzumab, and purine analogues (p = 0.012). Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. These data suggest that increased age and use of purine analogues are main risk factors for increased mortality of COVID-19 in patients with lymphoid malignancies. Obinutuzumab further increases the risk of prolonged disease, but not of death, in comparison to rituximab. Epidemiological considerations should be taken into account when choosing the appropriate antineoplastic therapy for patients with lymphoid malignancies.

Hyperuricemia is characterised by high blood levels of uric acid, and it can degenerate into gout when monosodium urate crystals precipitate in joints and other tissues. Uric acid is produced during the catabolism of xanthine by the enzyme xanthine oxidase (XO), which is the primary therapeutic target in gout treatment. Current XO inhibitors approved to treat gout, such as allopurinol and febuxostat, suffer from serious adverse effects, creating the need for new drug molecules. Three libraries comprising 75 purine analogues were designed using a 1,2,4-triazolo[1,5-a]pyrimidine scaffold, synthesised and tested in vitro as potential XO inhibitors. The screening identified that 23 compounds exhibited better inhibitory activity than allopurinol, with 2-(4-isopropoxyphenyl)-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid being 23 times more potent. Enzyme kinetics studies and molecular docking simulations were performed on the most active compounds to identify the mechanism of action and intermolecular interactions between the active site of XO and the inhibitors. The most potent compounds exhibited a mix-type inhibition mechanism and were predicted to interact with the same amino acid residues as allopurinol. These novel purine analogues are promising hits for further new lead development among purine-like drug XO inhibitors with therapeutic potential in the treatment of hyperuricemia and associated diseases., (© 2024 Wiley‐VCH GmbH.)

Purine analogues are important therapeutic tools due to their affinity to enzymes or receptors that are involved in critical biological processes. In this study, new 1,4,6-trisubstituted pyrazolo[3,4-b]pyridines were designed and synthesized, and their cytotoxic potential was been studied. The new derivatives were prepared through suitable arylhydrazines, and upon successive conversion first to aminopyrazoles, they were converted then to 1,6-disubstituted pyrazolo[3,4-b]pyridine-4-ones; this served as the starting point for the synthesis of the target compounds. The cytotoxic activity of the derivatives was evaluated against several human and murine cancer cell lines. Substantial structure activity relationships (SARs) could be extracted, mainly concerning the 4-alkylaminoethyl ethers, which showed potent in vitro antiproliferative activity in the low μM level (0.75–4.15 μΜ) without affecting the proliferation of normal cells. The most potent analogues underwent in vivo evaluation and were found to inhibit tumor growth in vivo in an orthotopic breast cancer mouse model. The novel compounds exhibited no systemic toxicity; they affected only the implanted tumors and did not interfere with the immune system of the animals. Our results revealed a very potent novel compound which could be an ideal lead for the discovery of promising anti-tumor agents, and could also be further explored for combination treatments with immunotherapeutic drugs.

Summary: For a disease initially described in 1958 as a leukaemic reticulo‐endotheliosis associated with poor outcomes, we have come a long way in our understanding of Hairy cell leukaemia. The vast majority of patients diagnosed with this rare, often diagnostically challenging, leukaemia can now expect a lifespan that is similar to the general population. This article covers some of the highlights from the last 6 decades that have led to our current understanding of this fascinating leukaemia ‐ from elucidation of its B‐cell origin to discovery of the almost universal occurrence of the BRAF V600E mutation; from the initial successes reported with splenectomy to the more recent development of targeted therapies such as Vemurafenib and Moxetumomab Pasudotox. It also pays tribute to some of the outstanding research in this field focusing particularly on the significant contributions made by the clinical and scientific community in the UK. [ABSTRACT FROM AUTHOR]

Some more new fluorine substituted pyrazolo[4,3-e][1,2,4]triazine derivatives (2–5), 7, 10, 14, 17 have been synthesized derived from hydrazinolysis of N-acyl/aroyl/dithioic formamido-2,3-dimethyl-1-phenyl-pyrazolo-5-ones which are obtained from 4-aminoantipyrine 1. The enzymatic assays (cellobaise activity) of the new products have been evaluated.

The rapid increase in antibiotic-resistant bacteria has emphasized the urgent need to identify new treatments for bacterial infections. One attractive approach, reducing the need for expensive and time-consuming clinical trials, is to repurpose existing clinically approved compounds for use as antibacterial agents. Nucleoside analogues are commonly used for treating viral and fungal infections, as well as for treating cancers, but have received relatively little attention as treatments for bacterial infections. However, a significant number of clinically approved derivatives of both pyrimidines and purines including halogenated, thiolated, and azolated compounds have been shown to have antibacterial activity. In the small number of studies carried out to date, such compounds have shown promise in treating bacterial infections. Here, we review the mechanisms of action and antibacterial activities of nucleoside analogues that can potentially be repurposed for treating infections as well as considering possible limitations in their usage.

Novel substituted purine isosters, were designed and synthesized as potential inhibitors of the Epidermal Growth Factor Receptor (EGFR). The compounds were rationally designed through bioisosteric replacement of the central quinazoline core of lapatinib, an approved drug that inhibits both EGFR and HER2, another important member of this family of receptors. The new target molecules were evaluated as inhibitors of receptor phosphorylation at the cellular level, for their direct inhibitory action on the intracellular receptor kinase domain and for their cytotoxicity against the non-small cell lung cancer cell line A549 and breast cancer HCC1954, cell lines which are associated with overexpression of EGFR and HER2, respectively. The most potent derivatives were further studied for their cellular uptake levels and in vivo pharmacokinetic properties. One compound (23) displayed a noteworthy pharmacokinetic profile, and higher intracellular accumulation in comparison to lapatinib in the A549 cells, possibly due to its higher lipophilicity. This lead compound (23) was assessed for its efficacy in an EGFR positive xenograft model, where it successfully inhibited tumor growth, with a similar efficacy with that of lapatinib and with minimal phenotypic toxicity. Image 1 [ABSTRACT FROM AUTHOR]

The rapid increase in antibiotic-resistant bacteria has emphasized the urgent need to identify new treatments for bacterial infections. One attractive approach, reducing the need for expensive and time-consuming clinical trials, is to repurpose existing clinically approved compounds for use as antibacterial agents. Nucleoside analogues are commonly used for treating viral and fungal infections, as well as for treating cancers, but have received relatively little attention as treatments for bacterial infections. However, a significant number of clinically approved derivatives of both pyrimidines and purines including halogenated, thiolated, and azolated compounds have been shown to have antibacterial activity. In the small number of studies carried out to date, such compounds have shown promise in treating bacterial infections. Here, we review the mechanisms of action and antibacterial activities of nucleoside analogues that can potentially be repurposed for treating infections as well as considering possible limitations in their usage. [ABSTRACT FROM AUTHOR]

Summary: In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well‐tolerated in previously untreated patients with advanced‐stage, indolent non‐Hodgkin lymphoma (iNHL). After a median patient follow‐up of more than 108 months, we performed an intent‐to‐treat analysis of our 83 participants. Progression‐free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten‐year PFS rates for those with beta‐2‐microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10‐year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long‐term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10‐year follow‐up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL. [ABSTRACT FROM AUTHOR]

The easy, convenient and high yielding preparation of new thioglycosides incorporating mercaptopyrazolo[1,5-a]pyrimidine moieties from readily accessible starting materials has been reported. The main step of this protocol is the formation of 7-mercaptopyrazolo[1,5-a]pyrimidine-6-carbonitrile derivatives4a-dby condensation of sodium 2-cyano-3-ethoxy-3-oxoprop-1-ene-1,1-bis(thiolate)1with 4-(aryldiazenyl)-1H-pyrazole-3,5-diamines3a-dto form target compounds4a-d, which coupled with tetra-O-acetyl-α-D-glycopyranosyl bromides5a,bin the presence of basic medium to provide the corresponding product purine thioglycoside analogs6a-h. Ammonolysis of the latter compounds6a-dat ambient temperature for 10 minutes, led to the free glycoside derivatives7a-h, which were obtained in approximately quantitative yields. Their structures were created based on the spectroscopic and elemental data. [ABSTRACT FROM AUTHOR]

Inhibition of parasite metabolic pathways is a rationale for new chemotherapeutic strategies. The pyrimidine and purine salvage pathways are thus targets against Leishmania donovani and L. infantum, causative agents of visceral human leishmaniasis and canine leishmaniosis. The antiproliferative effect of the pyrimidine analogues Cytarabine and 5-fluorouracil and of the purine analogues Azathioprine and 6-mercaptopurine was evaluated in vitro on the promastigote and the intracellular amastigote stages of the parasite. Cytarabine and 5-fluorouracil were the best inhibitors against promastigotes, whereas 5-fluorouracil and azathioprine displayed the best efficacy against the amastigote stage. The ultrastructural study showed an important cytoplasmic vacuolization and with azathioprine and 5-fluorouracyl, a mitochondrial swelling and appearance of autophagosome-like structures. Alterations of the kinetoplast were also observed with 5-fluorouracil, all these damages eventually resulting in an autolysis process that triggered the subsequent death of the intracellular parasites. [ABSTRACT FROM AUTHOR]

While working with G418-resistant stably transfected cells, we realized the neomycin resistance (NeoR) gene, which encodes the aminoglycoside-3'-phosphotransferase-IIa [APH(3')-IIa], also confers resistance to the nucleoside analog fludarabine. Fludarabine is a cytostatic drug widely used in the treatment of hematologic and solid tumors, as well as in the conditioning of patients before transplantation of hematopoietic progenitors. We present evidence that NeoR-transfected cells do not incorporate fludarabine, thus avoiding DNA damage caused by the drug, evidenced by a lack of FANCD2 monoubiquitination and impaired apoptosis. A screening of other nucleoside analogs revealed that APH(3')-IIa only protects against ATP purine analogs. Moreover, APH(3')-IIa ATPase activity is inhibited by fludarabine monophosphate, suggesting that APH(3')-IIa blocks fludarabine incorporation into DNA by dephosphorylating its active fludarabine triphosphate form. Furthermore, overexpression of the catalytic subunit of the eukaryotic kinase PKA, which is structurally related to APHs, also provides resistance to fludarabine, anticipating its putative utility as a response marker to the drug. Our results preclude the use of Neo marker plasmids in the study of purine analogs and unveils a new resistance mechanism against these chemotherapeuticals. [ABSTRACT FROM AUTHOR]

Patients with hairy cell leukaemia ( HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition. The CD22-targeted immunoconjugate moxetumomab pasudotox and BTK inhibitor ibrutinib also achieve responses in relapsed and refractory patients. HCL variant and the IGHV4-34 molecular variant of HCL lack BRAF mutation and have inferior outcomes with standard purine analogue therapy. The addition of rituximab to purine analogues achieves very high rates of minimal residual disease-negative complete remission and improves outcomes for patients with HCL variant. Given the rarity of HCL, optimal integration of novel therapies into treatment algorithms will require well-designed, collaborative studies. [ABSTRACT FROM AUTHOR]

Some more new fluorine substituted pyrazolo[4,3-e][1,2,4]triazine derivatives (2 – 5) , 7 , 10 , 14 , 17 have been synthesized derived from hydrazinolysis of N-acyl/aroyl/dithioic formamido-2,3-dimethyl-1-phenyl-pyrazolo-5-ones which are obtained from 4-aminoantipyrine 1 . The enzymatic assays (cellobaise activity) of the new products have been evaluated. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a malignant lymphoproliferative disorder characterized by the presence of a high level of serum monoclonal IgM and a lymphoplasmacytic infiltrate in the bone marrow. This meta-analysis sought to assess the effectiveness of the different treatments for WM tested in published trials using the response rate (RR) as the main outcome measure. Forty-six articles (1409 patients) identified were entered in a variable effects model meta-analysis of proportions (rates and sample sizes). A greater response to treatment was produced in patients treated with a combination of 2+ drugs (RR = 73%; 95%CI: 62, 83; p < 0.01) than in those receiving monotherapy with rituximab (RR = 44%; 95%CI: 34, 55; p < 0.01) or a purine analogue [61% (95%CI: 43, 78; p < 0.01) for cladribine and 53% (95%CI: 34, 72; p < 0.01) for fludarabine]. The combination rituximab + cladribine emerged as particularly effective (RR = 87%; 95%CI: 78, 94; p < 0.01), slightly more effective than rituximab + bortezomib/dexamethasone (RR = 84%; 95%CI: 79, 88; p < 0.01) and rituximab + cyclophosphamide/dexamethasone [RR = 81% (95%CI: 72, 88; p < 0.01)]. Our results are in overall agreement with treatment recommendations from the seventh International Workshops on WM. Our findings are limited by the fact that we could not analyze progression-free survival (PFS). More phase II/III trials are needed to corroborate promising recent findings with bendamustine and carfilzomib and further research are needed to standardize recommendations based on maximum treatment efficacy combined with lowest toxicity, differentiation between first vs second line treatment, or long-term follow up after treatment. [ABSTRACT FROM AUTHOR]

Elderly patients with chronic lymphocytic leukemia (CLL) are underrepresented in trials evaluating fludarabine, cyclophosphamide, and rituximab (FCR). We assessed four cycles of FCR with two additional rituximab doses on day 14 of cycles 1 and 2 in 194 untreated CLL patients > 65 years (median age 71.2) without del17p. Four FCR cycles were administered to 90.7% (176/194), with (n= 74) or without (n= 102) dose-delay and/or dose-reduction. A total of 50% grade 3/4 neutropenia occurred after each cycle. Only 6.2% cycles were associated with severe infection. Complete remission (CR) was achieved in 19.7%, and partial remission (PR) in 73.9% of patients. Minimal residual disease (MRD) was negative in 36.7%. Overall survival at 36 months was estimated at 87.4%. Oral FC and dose-dense rituximab is feasible and active in fit elderly CLL patients. However, myelosuppression is significant and frequent dose adaptations are required implying that these results cannot be generalized to unfit or frail elderly CLL. [ABSTRACT FROM PUBLISHER]

Hairy cell leukemia (HCL) is an uncommon B-cell lymphoid neoplasia, representing 2---3% of all leukemias. It is more common in men, with a median age at diagnosis of 52 years. The hair-like projections on its surface are its principal characteristic. Although its etiology has not been established, the recent gene sequencing of HCL identified the presence of the BRAF V600E mutation, absent in other malignant neoplasias of the lymph cells. The clinical course of the disease is usually indolent. The majority of patients initially present weakness and fatigue, pancytopenia and splenomegaly. HCL must be distinguished from other indolent lymphoid neoplasias such as prolymphocytic leukemia, splenic marginal zone lymphoma, the variant of HCL (HCLv), and mantle cell lymphoma. Peripheral blood flow cytometer is essential for the detection of CD11c, CD19, CD20, CD22, CD25, and CD10, as well as a bone marrow aspirate to detect immunophenotypes. In addition, a bone biopsy is useful to perform an immunohistochemistry analysis for TRAP, DBA-44 and A1 annexin. Purine analogues remain the first line of treatment. However, interferon and rituximab are a valid option, if the ideal treatment is unavailable. New discoveries in the pathophysiology of HCL have brought the creation of pharmaceuticals with distinct therapeutic targets. These pharmaceuticals are currently undergoing testing. [ABSTRACT FROM AUTHOR]

Background and aims: Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment. Methods: In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months. Results: We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died. Conclusions: Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients. [ABSTRACT FROM AUTHOR]

The outcome of patients with follicular lymphoma has substantially improved in recent years, mainly due to the widespread use of the monoclonal antibody rituximab and partially due to autologous and allogeneic transplantation, and the introduction of new drugs and to the improvement in diagnostic accuracy. The choice of therapy is still based on patient characteristics, extension of disease and clinical prognostic factors. The majority of patients in need of treatment are still treated with cytotoxic agents in combination with rituximab; nevertheless a number of new agents, which are active in this disease, have recently been developed. It has yet to be determined, whether they will partly or completely replace chemotherapy in the near future. This review focuses on the role and the choice of chemotherapy in different clinical situations of follicular lymphoma, in a time when chemotherapy-free treatment becomes more and more of a topic of discussion. [ABSTRACT FROM PUBLISHER]

Synthesis of several pryrazolo[4,3-e][1,2,4]-triazines is described. Theabsorption spectrum of some 5-substituted derivatives was found to extend to the visibleregion. These compounds were found to inhibit some enzymes of purine metabolism, likexanthine oxidase or bacterial purine-nucleoside phosphorylase with Ki values in the 10-3 –10-5 M range.

The article offers information on the hairy-cell leukaemia (HCL) which is a B-cell lymphoproliferative disorder with the morphological, molecular and immunophenotypic profile. It mentions that markers are determined by flow cytometry (FC), that allows an accurate diagnosis and minimal residual disease (MRD) monitoring.

Background: Cancer cells restrain apoptotic and senescence pathways through intracellular heat shock protein 70 (Hsp 70). These cells aid stimulus-independent growth, and their higher metabolism rate requires Hsps. Hsps compensate abnormally increased substrate protein folding rate of cancer cells., Objective: Misfolding of substrate proteins especially signaling substrate proteins, may not function properly. Therefore, Hsp70 folds these substrate proteins into their native-fully functional states, and this mode of action helps cancer cell survival., Methods: Targeting Hsps is promising cancer therapy, and in this study, 6,8,9-trisubstituted purine derivatives were designed and synthesized to inhibit Hsp70 and drive cancer cells to apoptosis. Further, oncogenic stimuli through inhibitors can induce an irreversible senescent state and senescence is a barrier to transformation., Results: Hsp70 helps cancer cells to bypass the cellular senescence program, however, binding of N6-(4- isopropylaniline) analogue (7) depletes Hsp70 function as evidenced by aggregation assay and Hsp70 depletion induces senescence pathway., Conclusion: The purine-based inhibitor-compound 7 effectively inhibits MCF-7 cell line. Moreover, the therapeutic potential with regard to the senescence-associated secretory phenotype has complementary action. Dual action of the inhibitor not only drives the cells to apoptosis but also force the cells to be in the senescence state and provides promising results specially for luminal A type breast cancer therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A wide range of natural purine analogues was used as probe to assess the mechanism of recognition by the wild-type (WT) E. coli purine nucleoside phosphorylase (PNP) versus its Ser90Ala mutant. The results were analyzed from viewpoint of the role of the Ser90 residue and the structural features of the bases. It was found that the Ser90 residue of the PNP 1) plays an important role in the binding and activation of 8-aza-7-deazapurines in the synthesis of their nucleosides, 2) participates in the binding of α- D-pentofuranose-1-phosphates at the catalytic site of the PNP, and 3) catalyzes the dephosphorylation of intermediary formed 2-deoxy-α- D-ribofuranose-1-phosphate in the trans-2-deoxyribosylation reaction. 5-Aza-7-deazaguanine manifested excellent substrate activity for both enzymes, 8-amino-7-thiaguanine and 2-aminobenzothiazole showed no substrate activity for both enzymes. On the contrary, the 2-amino derivatives of benzimidazole and benzoxazole are substrates and are converted into the N1- and unusual N2-glycosides, respectively. 9-Deaza-5-iodoxanthine showed moderate inhibitory activity of the WT E. coli PNP, whereas 9-deazaxanthine and its 2′-deoxyriboside are weak inhibitors. [ABSTRACT FROM AUTHOR]

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Hairy cell leukaemia (HCL) is a rare chronic indolent lymphoproliferative disease of B-lymphocytes. It always infiltrates the spleen, bone marrow or other organs and is also present in the peripheral blood in more than 95% of cases. The disease takes its name from its characteristic wrinkled surface with hair-like projections. The prognosis of this infaust diagnosis has dramatically changed since the 1980s through more precise diagnosis and efective treatment with purine analogues (1984, 2-deoxycoformy-cine (2-dCF); 1990, 2-chlorodeoxyadenosine (2-CdA)). In our group of 38 patients, we confrmed the diagnostic possibilities and their accuracy; in addition to morphological examination, these include fow cytometric detection of typical surface CD antigens and immunohistochemical recognition of hairy cells in the trephine biopsy. The treatment percentage in the number of response rates (RRs) (100%), complete remissions (CRs) (79%) and overall survival of patients is comparable with previously known data. Overall survival rate without symptoms of disease for more than 10 years after treatment is 87% (33/38). The presence and quantity of minimal residual disease (MRD) after frst-line treatment in bone marrow determine subsequent progression or relapse of the disease, sometimes even occurring many years after the treatment. Probably some new pharmacotherapeutical possibilities (monoclonal antibodies, immunotoxins, tyrosine kinase inhibitors or inhibitors of B-Raf enzyme) could demonstrate the ability to eliminate MRD and cure it in relapsed patients or patients refractory to purine analogues. HCL has become an oncological disease with a relatively good prognosis and long-term survival after standard treatment with purine analogues despite the persistence of indolent MRD in the bone marrow at varying degree of residual infiltration intensity. [ABSTRACT FROM AUTHOR]

Simple Summary: Classic hairy cell leukemia (HCL) is a rare, chronic B-cell malignancy with long-term remissions after standard treatment with purine analogues introduced in the 1990s. Although nearly all patiently ultimately relapse after up to 20 years from therapy requiring retreatment, overall survival prognosis remains insufficiently defined as life expectancyhas rarely been corrected for that of the general population. The aim of this single-center retrospective analysis was to report the long-term clinical outcomes of 83 consecutive HCL patients and compare overall survival with a matched cohort from the general population. We show that HCL patients may look forward to a normal lifespan when treated with purine analogues irrespectively of their pretreatment history, age at diagnosis, or whether they were treated until or after the year 2000. Classic hairy cell leukemia (HCL) is an uncommon hematologic malignancy characterized by an excellent prognosis since purine analogues (PA), such as cladribine (2-CdA), have been introduced in the 1990s. However, most data on long-term outcomes is gathered from patients treated with PA first-line or include limited information on previous treatment outcomes, i.e., Interferon-α (IFN-α). Survival curves from previous series did not reach a plateau, indicating that nearly all patients ultimately relapse. Yet, overall survival (OS) data were rarely corrected for life expectancy of the general population. We here report 83 consecutive HCL patients treated between 1983 and 2017 at the University Center in Innsbruck, Austria. Median follow-up was 170 months (1–498). IFN-α, the first-line treatment of choice before 1990, was administered to 24 patients, achieving an overall response rate (ORR) of 86% and an unconfirmed complete remission (CRu) in 23%. All these patients relapsed after a median progression-free survival (PFS) of 30 months (3–80), but either remained drug-sensitive upon re-exposure to IFN-α or were successfully salvaged with PA. All 42 patients exposed to first-line 2-CdA responded (ORR of 100%). Sixteen patients received two to four successive courses of PA with a continuous decrease in the response quality (CRu rate 85.7% 1st-line vs. 41.5% 3rd-line treatment). Median PFS was not reached in both treatment-naïve patients and those retreated at first relapse. Although pretreatment with IFN-α was associated with a shortened median PFS of 81 months (43–118) after PA therapy, this tendency of inferior PFS did not result in inferior OS. OS of all 83 patients was excellent and equivalent to that of age-, sex-, and diagnostic period-matched controls from the Tyrolean general population (standardized mortality ratio 0.8), regardless of their age at diagnosis or whether they were diagnosed until or after the year 2000. These results confirm that HCL patients may look forward to a normal lifespan when treated with PA irrespective of their pretreatment history. [ABSTRACT FROM AUTHOR]

Nearly all information about patients with chronic lymphocytic leukaemia ( CLL) who develop diffuse large B-cell lymphoma [ Richter syndrome ( RS)] is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL between January 2000 and July 2011. Individuals who developed biopsy-proven RS during follow-up were identified. After a median follow-up of 4 years, 37/1641 (2·3%) CLL patients developed RS. The rate of RS was approximately 0·5%/year. Risk of RS was associated with advanced Rai stage at diagnosis ( P < 0·001), high-risk genetic abnormalitites on fluorescence in situ hybridization ( P < 0·0001), unmutated IGHV ( P = 0·003), and expression of ZAP70 ( P = 0·02) and CD38 ( P = 0·001). The rate of RS doubled in patients after treatment for CLL (1%/year). Stereotyped B-cell receptors (odds-ratio = 4·2; P = 0·01) but not IGHV4-39 family usage was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS three-fold (odds-ratio = 3·26, P = 0·0003). Median survival after RS diagnosis was 2·1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0·5 years, 2·1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed. [ABSTRACT FROM AUTHOR]

Abstract: Novel purine analogues bearing nitrate esters were designed and synthesized in an effort to develop compounds triggering endogenous cardioprotective mechanisms such as ischemic preconditioning (IPC) or postconditioning (PostC). The majority of the compounds reduced infarct size compared to the control group in anesthetized rabbits, whereas administration of the most active analogue 16 at a dose of 3.8μmol/kg resulted on a significant reduction of infarct size, compared to PostC group (13.4±1.9% vs 26.4±2.3%). These findings introduce a novel class of promising pharmacological compounds that could be used as mimics or enhancers of PostC. [Copyright &y& Elsevier]

Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A, A, A, and A). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A, A, or A receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A receptors. Clofarabine and cladribine both bound to the A receptor with a K of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A receptor with a K of 10 μM, and none of these compounds bound to the A receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A receptor. In addition, clofarabine, cladribine, and fludarabine were A agonists (IC 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes ( K > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs. [ABSTRACT FROM AUTHOR]

novel platinum(IV) coordination compound with 6-mercaptopurine (6-Hmp) has been synthesised and characterised by IR and NMR spectroscopy. Spectroscopic parameters indicate the presence of two chelate (S-6, N-7) monodeprotonated ligands and two chloride ions in the coordination sphere of [PtCl(6-mp)] · HO ( I). Two Pt(IV) coordination compounds, [PtCl(6-mp)] · HO ( I) and [PtCl(dbtp)] ( II), were used in the in vivo test against B16 mouse melanoma tumours. Cytotoxic activity of compound II against the tumour cells was found to be high (LC = 2.6 μM, LC = 17.0 μM, LC = 58.0 μM) compared to that of cisplatin. [ABSTRACT FROM AUTHOR]

The WHO classification recognises three distinct disorders of large granular lymphocytes: T-cell large granular lymphocytic leukaemia (T-LGL), chronic lymphoproliferative disorders of NK-cells (CLPD-NK) and agressive NK-cell leukaemia. Despite the different cell of origin, there is considerable overlap between T-LGL and CLPD-NK in terms of clinical presentation and therapy. Many patients are asymptomatic and do not require treatment. Therapy, with immunosuppressant agents such as low dose methotrexate or ciclosporin, is usually indicated to correct cytopenias. In contrast, aggressive NK-cell leukaemia and the rare CD56 aggressive T-LGL leukaemia follow a fulminant clinical course, affect younger individuals and require more intensive combination chemotherapy followed by allogeneic stem cell transplant in eligible patients. The relative rarity of these disorders means that there have been few clinical trials to inform management. However, there is now considerable interest in the pathogenesis of the chronic LGL leukaemias and this has stimulated early trials to evaluate novel agents which target the dysregulated apoptotic pathways characteristic of this disease. [ABSTRACT FROM AUTHOR]

In this study, we attempted to assess the interactions of resveratrol, a natural compound present in various plant species, with the purine analogues fludarabine and cladribine in terms of their effects on DNA damage and apoptosis in chronic lymphocytic leukemia (CLL) cells. The experiments were performed ex vivo using short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed the expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (γH2AX) and activated ATM kinase, which are reporters of DNA damage. The results of our study revealed that resveratrol induced apoptosis in CLL cells in a tumor-specific manner but did not affect non-leukemic cells, and apoptosis was associated with a decreased BCL2/BAX ratio. Here, we report for the first time that both resveratrol + fludarabine and resveratrol + cladribine caused a higher rate of apoptosis in comparison to the rate caused by a single drug. The percentage of apoptotic cells induced by resveratrol alone was higher in the group of patients with better prognostic markers than in those with worse prognostic markers. However, the rates of apoptosis caused by resveratrol combined with purine analogues were independent of ZAP-70 and CD38 expression and the clinical state of the disease; they were only dependent on the presence of high-risk cytogenetic abnormalities. We also observed an increase in γH2AX expression together with a rise in activated ATM in most of the analyzed samples. The obtained results indicate that resveratrol might warrant further study as a new therapeutic option for CLL patients. This naturally occurring substance may be used as a single agent, especially in older persons for whom there are some limitations for the use of aggressive treatment. On the other hand, a lower purine analogue dose could potentially be used in combination with resveratrol because of their combined effect. One of the mechanisms of action of resveratrol is the induction of DNA damage, which ultimately leads to apoptosis. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with variable clinical course and prognosis. Therefore, the role of prognostic factors is very important, especially for identifying the group of patients who require intensive treatment. The aim of this study was to assess whether the rate of apoptosis caused by purine analogues differs between patients with better or worse prognostic factors. The experiments were preformed in cultures of blood and bone marrow obtained from CLL patients. The cultures were supplemented with cladribine and fludarabine. We determined the percentage of caspase-3-positive cells and the BCL-2/BAX ratio, and subsequently these apoptosis markers were correlated with the expression of ZAP-70 and CD38, lymphocyte counts, lactate dehydrogenase and β2-microglobulin levels and clinical stage according to the Rai classification. The results showed that bone marrow cells are more sensitive to apoptosis caused by purine analogues than cells derived from blood, supporting the idea that these two compartments have different proliferative statuses. The cells from ZAP-70-positive patients seem to enter apoptosis more readily than those from ZAP-70-negative patients; thus, ZAP-70-positive patients are more likely to benefit from treatment with purine analogues. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary: Chronic lymphocytic leukaemia is a common lymphoid malignancy with a variable clinical course. While some patients never require treatment or can be managed effectively with palliative chemotherapy, others experience early disease progression and death. The development of new prognostic markers has helped in the identification of patients with high risk disease, even among those diagnosed at early stage. Recent prospective trials have established chemo-immunotherapy combinations as the new standard of care for CLL patients requiring therapy. Unfortunately, patients whose tumour cells have certain genomic aberrations, such as a chromosome 17 deletion, have a disease that is frequently refractory to conventional therapy and should have their treatment tailored accordingly. Younger patients with high risk disease should be referred for allogeneic haematopoietic cell transplantation if they have an appropriate donor. For the remaining high risk patients, a number of new compounds are emerging, which could lead to further improvement in their outcome. [Copyright &y& Elsevier]

Chronic lymphocytic leukemia (CLL) is dramatically increased in patients above the age of 65 years up to an incidence rate of 22-30/100 000. Although elderly patients represent the largest group of CLL patients they are clearly underrepresented in clinical trials. One important prognostic factor in the elderly is the burden of comorbidity. Survival is significantly impaired in CLL patients with multiple comorbidities (≥2) or with severe comorbidity (Charlson score ≥2). Therefore, not only age but also the incidence and burden of comorbidity should influence the choice of treatment strategy for every patient individually. A reliable tool for measuring comorbidity is the Cumulative Illness Rating Scale. The German CLL Study Group (GCLLSG) has used this tool within their clinical trials to distinguish between physically fit and non-fit patients. Although chlorambucil is still the standard treatment of choice in non-fit patients, dose-reduced purine analogue-based combination therapies with or without immunotherapy are currently investigated within clinical trials. Because full-dosed combination treatment might cause increased toxicity rates in relapse situation, dose-reduced combination therapies should be considered in this situation. An adequate supportive treatment is necessary for the prevention of toxicities as well as for the improvement of health-related quality of life. In summary, the treatment decision in elderly CLL patients is carefully to be made in each patient individually considering not only the stage and risk factors of the disease but also the patients' physical condition and social environment. [ABSTRACT FROM AUTHOR]

For oncologists and their patients, antimetabolites are cytotoxic agents that no longer hold any secrets. What cancer patient hasn’t received, or won’t eventually receive, 5-FU or MTX during the course of his or her illness? Would it be taking a chance to try to write news about them? It’s a challenge to talk to you about what’s happening with these drugs in 2007 because the literature is abundant. Imagine: 106 clinical trials of pemetrexed are listed on Clinicaltrials. gov (clinicaltrials-nccs.nlm.nih.gov), as of 30 August 2007! Of the three classes of antimetabolites, without being exhaustive, we will give you the latest news, for old molecules (let’s not be afraid of words) as well as those under development. [ABSTRACT FROM AUTHOR]

Abstract: Plasmodium falciparum causes one of the deadliest forms of malaria and resistance to the currently available drugs makes it imperative to develop new, safe and potent drugs. Parasites such as P. falciparum are unable to synthesise purines de novo and to this end often have multiple purine uptake and salvage systems. With this in mind, we have designed and synthesised libraries of purine analogues as potential anti-malarial agents. Herein, we report three compounds with promising activity against the highly chloroquine-resistant VS1 P. falciparum namely: N 6-hydroxyadenine (1c), 2-amino-N 6-aminoadenosine (2b) and 2-amino-N 6-amino-N 6-methyladenosine (4b). [Copyright &y& Elsevier]

Abstract: Brain efflux systems export such conjugated metabolites as glutathione (GSH) and glucuronate conjugates, generated by the detoxification process, from the brain and serve to protect the brain from harmful metabolites. The intracerebral injection of a radiolabeled conjugate is a useful technique to assess brain efflux systems; however, this technique is not applicable to humans. Hence, we devised a novel noninvasive approach for assessing GSH-conjugate efflux systems using positron emission tomography. Here, we investigated whether or not a designed proprobe can deliver its GSH conjugate into the brain. Radiolabeled 6-chloro-7-methylpurine (7m6CP) was designed as the proprobe, and [14C]7m6CP was prepared by the reaction of 6-chloropurine with [14C]CH3I as a model of [11C]CH3I. The radiochemical yield and purity of [14C]7m6CP were 10–20% and greater than 99%, respectively. High brain uptake (0.8% ID/g) at 1min was observed, followed by gradual radioactivity clearance from the brain for 5–60min after the injection of [14C]7m6CP into rats. Analysis of metabolites confirmed that the presence of [14C]7m6CP was hardly observed, and 80% of the radioactivity was identical to its GSH conjugate for 15–60min. The brain radioactivity was single-exponentially decreased during the period of 15–60min post-injection of [14C]7m6CP, and the first-order efflux rate constant of the conjugate, estimated from the slope, was 0.0253min−1. These results showed that (1) [14C]7m6CP readily entered the brain, (2) it efficiently and specifically transformed to the GSH conjugate within the brain, and (3) after [14C]7m6CP disappearance, the clearance of radioactivity represented the only efflux of GSH conjugate. We conclude that 7m6CP can deliver the GSH conjugate into the brain and would be useful for assessing GSH-conjugate efflux systems noninvasively. [Copyright &y& Elsevier]

Cytosolic 5′nucleotidase II (cN-II) catalyses both the hydrolysis of a number of nucleoside monophosphates (e.g., IMP + H2O→inosine + Pi), and the phosphate transfer from a nucleoside monophosphate donor to the 5′position of a nucleoside acceptor (e.g., IMP + guanosine →inosine + GMP). The enzyme protein functions through the formation of a covalent phosphoenzyme intermediate, followed by the phosphate transfer either to water (phosphatase activity) or to a nucleoside (phosphotransferase activity). It has been proposed that cN-II regulates the intracellular concentration of IMP and GMP and the production of uric acid. The enzyme might also have a potential therapeutic importance, since it can phosphorylate some anti-tumoral and antiviral nucleoside analogues that are not substrates of known kinases. In this review we summarise our recent studies on the structure, regulation and function of cN-II. Via a site-directed mutagenesis approach, we have identified the amino acids involved in the catalytic mechanism and proposed a structural model of the active site. A series of in vitro studies suggests that cN-II might contribute to the regulation of 5-phosphoribosyl-1-pyrophosphate (PRPP) level, through the so-called oxypurine cycle, and in the production of intracellular adenosine, formed by ATP degradation. [ABSTRACT FROM AUTHOR]

Abstract: Deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) catalyze the first step in the intracellular cascade of fludarabine (2-fluoroadenine-β-d-arabinofuranoside) and cladribine (2-chlorodeoxyadenosine) phosphorylation, which leads to activation of these prodrugs, commonly used for treatment of chronic lymphocytic leukemia (CLL). Thus, resistance to nucleoside analogues may primarily be due to low levels of deoxynucleoside kinase activity. The purpose of this study was to investigate the activity profiles of dCK and dGK and characterize the possible relationship between the levels of dCK enzymatic activities and mRNA levels in B-CLL cells from untreated patient samples in an attempt to determine the best approach for predicting sensitivity to nucleoside analogues and thereby optimizing treatment of CLL. For this purpose, dCK and dGK analyses were done in blood cells from 59 untreated symptomatic patients with CLL. The dGK activity towards 2-chlorodeoxyadenosine was significantly lower than of dCK (median 73pmol/mgprotein/min (85–121, 95% CI) versus 353pmol/mgprotein/min (331–421)). The median dCK mRNA level was 0.107 (0.096–0.120, 95% CI). There was a lack of correlation between the activities of dCK and dGK, which indicates that these proteins are regulated independently. We also found that the dCK and dGK activity measurement towards their endogenous substrates were comparable to the nucleoside analogues tested. Such variations in enzyme activities and mRNA levels may well explain differences in clinical responses to treatment. There was no correlation between the levels of dCK mRNAs and enzymatic activities using a quantitative real-time PCR procedure. Sequencing of dCK mRNA did not reveal alternate splicing or mutations in the coding region. The relation between activity and mRNA levels was studied by short interfering RNA (siRNA) method, which showed that in the siRNA treated cells the down-regulation of dCK expression, and activity followed each other. However, in control cells the mRNA levels remained stable but the protein activity markedly decreased. These data demonstrate that the dCK activity is not reflected by dCK mRNA expression that indicates a post-translational mechanism(s). [Copyright &y& Elsevier]