Efficacy and Safety of Hydroxychloroquine Sulphate In Chronic Lymphocytic Leukemia: Clinical Trial Experience In Untreated Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1392-1392
Author(s):  
Shih-Shih Chen ◽  
Matthew Kaufman ◽  
Angelica Caramanica ◽  
Rajendra N Damle ◽  
Peter Garofalo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cell Proliferation ◽  
Disease Progression ◽  
Repeated Measures ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Vitro Assay ◽  
Blood Concentrations ◽  
Absolute Lymphocyte Counts

Abstract Abstract 1392 Background: Hydroxychloroquine (HCQ) has been used safely for many years for treatment of malaria, systemic lupus erythematosus and rheumatoid arthritis. It is known to have exerted immunomodulatory actions by affecting antigen presentation by macrophages and dendritic cells, DNA/RNA synthesis, and apoptosis in lymphocytes and endothelial cells. All of these actions can be attributed at least partially to the inactivation of endosomal acid proteases. CLL is the abnormal proliferation of a B lymphocyte clone. Based on the unique structural characteristics of the B-cell antigen receptor (BCR), at least some CLL cases probably results from ongoing antigen selection and stimulation. RNA and/or DNA from infection or cell apoptosis are candidate stimulants of this process. Binding of RNA and DNA to toll-like receptors (TLR 7 and 9) in endosomes is dependent on an acidic pH and can be prevented by HCQ due to its de-acidifiying effect. HCQ can also directly induce apoptosis in CLL cells through caspase 3 activation in vitro. We therefore hypothesized that administration of HCQ early in the disease would protect CLL patients from disease progression by eliminating these stimulatory TLR 7 and 9 signals. Methods: 22 CLL patients with no urgent need for treatment were enrolled in the clinical trial. Patients took HCQ 400 mg/day for 52 weeks. Clinical response was measured every 4 weeks by history, physical exam, and absolute lymphocyte counts. Additional blood samples were taken every 8 weeks for companion laboratory studies. Statistical analyses used include Fisher's Exact Test, Slopes analysis and Repeated measures analysis of variance on the log-transformed absolute lymphocyte counts (ALCs). Results: In total, 8 IGHV unmutated (U-CLL) and 14 mutated (M-CLL) patients were enrolled; 3 U-CLL and 10 M-CLL completed the full year of HCQ treatment. Five U-CLL patients were dropped from the study due to disease progression requiring CLL therapy. One M-CLL patient left for personal reasons. Three M-CLL patients are still continuing on HCQ therapy. Patient outcomes can be separated into three patterns based on ALC changes: 7 patients (6 M-CLL and 1 U-CLL) had stable counts throughout the trial; 12 patients (8 M-CLL and 4 U-CLL) had a fall in ALCs after treatment; and 3 patients (all U-CLL) developed increased ALCs. The response to HCQ in CLL is associated with Ig V mutation status of patients (P<.03). With some U-CLL patients having a worsening of disease; overall U-CLL patients have worse outcome than M-CLL (P<.045). Nevertheless in most instances, U-CLL patients did respond to HCQ with stabilization or fall in ALC initially, although this was followed at an average of 18–22 weeks with an increase in ALCs and in some instances a need for therapy. Maximum HCQ blood concentrations in healthy individuals receiving 400 mg/day HCQ orally are reported to range from 67–221 ng/ml. In vitro assay using samples collected at trial initiation indicated that direct CLL cytotoxicity occurred at levels ≥10 μg/ml; this value was similar for U- and M-CLL clones. Using a non-cytotoxic concentration of 1 μg/ml of HCQ, in vitro TLR9 ligand ODN2006 enhanced expression of TLR9 was diminished. The proliferation and activation of both U- and M-CLL was blocked completely, although concentrations of 10–100 ng/ml had a superior blocking effect on M-CLL than U-CLL clones. In vivo administration of HCQ blocked CLL cell proliferation initiated by ODN2006. In comparison with samples taken before HCQ administration, patient samples obtained after trial initiation responded to ODN2006 poorly. Interestingly, the type of CLL cell response to ODN2006 closely correlated with patient's ALC change. The least blocking of HCQ on cell proliferation was again observed in U-CLL patients, especially with the samples taken from the timepoint at which elevated ALCs were observed. Conclusion: In this clinical trial, oral administration of HCQ (400 mg/day) stabilized or decreased ALCs in the initial 18–22 weeks (of a 46–52 week regimen) in 91% of patients (14 M-CLL and 6-U-CLL). Subsequently, rising ALCs were observed in most of the U-CLL cases (n=4), and ALCs in M-CLL patients remain stabilized. Our in vitro evaluation suggests that an increased dose of HCQ might target TLR9 signaling better and thus improve outcome especially in U-CLL cases. Another possibility that warrants further study is that HCQ may have several actions on CLL cells leading to worse outcome of the disease. Disclosures: No relevant conflicts of interest to declare.

Enhanced In Vivo activation of Adoptively Transferred Genetically Targeted T Cells Following Cyclophosphamide Chemotherapy: Initial Results From a Phase I Clinical Trial Treating CLL Patients with Autologous CD19-Targeted T Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3436-3436
Author(s):  
Renier J. Brentjens ◽  
Daniel Hollyman ◽  
Jae Park ◽  
Elmer Santos ◽  
Raymond Yeh ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
High Efficiency ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Autologous Tumor

Abstract Abstract 3436 Poster Board III-324 Patient T cells may be genetically modified to express chimeric antigen receptors (CARs) targeted to antigens expressed on tumor cells. We have initiated a clinical trial treating chemotherapy-refractory chronic lymphocytic leukemia (CLL) patients with autologous T cells modified to express the 19-28z CAR targeted to the CD19 antigen expressed on most B cell malignancies. In the first cohort of this trial, patients were infused with the lowest planned dose of modified T cells alone. All patients treated in this cohort experienced low-grade fevers following modified T cell infusion, and 2 of 3 treated patients exhibited subjective and laboratory evidence of transient reductions in tumor burden. The first patient treated on the second cohort of this study received prior cyclophophamide chemotherapy followed by the same dose of modified T cells administered to the first cohort of patients. This patient experienced persistent fevers, dyspnea, hypotension, renal failure, and died 44 hours following modified T cell infusion, likely secondary to sepsis. Modified T cells were not detectable in the peripheral blood of treated patients at 1 hour following completion of T cell infusion. However, post mortem analyses revealed a rapid infiltration of targeted T cells into anatomical sites of tumor involvement. Serum levels of the inflammatory cytokines IL-5, IL-8, and GM-CSF, but not TNFα, markedly and rapidly increased following infusion of genetically targeted T cells in this patient, mirroring the in vitro cytokine secretion profile of this patient's T cells, and consistent with marked in vivo activation of the modified T cells. Similar cytokine signatures were not found in patients from the first cohort. Significantly, serum cytokine analyses from the second cohort patient revealed a marked increase in the pro-proliferative cytokines IL-2, IL-7, IL-12, and IL-15 following cyclophosphamide therapy, in contrast to the baseline levels found in the first cohort. This report demonstrates the high efficiency trafficking of CD19-targeted T cells and in vivo activation of T cells encoding a second generation CD28/zeta chain-based chimeric antigen receptor. Furthermore, these data highlight mechanisms whereby cyclophosphamide may generate an in vivo milieu that enhances the anti-tumor efficacy of autologous tumor targeted T cells. Disclosures No relevant conflicts of interest to declare.

Divergence in CD19-Mediated Signaling Unfolds Intra-Clonal Diversity in Chronic Lymphocytic Leukemia Which Correlates with Disease Progression

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4570-4570
Author(s):  
Yair Herishanu ◽  
Sigi Kay ◽  
Nili Dezorella ◽  
Chava Perry ◽  
Varda Deutsch ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Clonal Diversity ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Fraction ◽  
Akt Phosphorylation

Abstract Abstract 4570 Emerging data on intra-clonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. Here we report intra-clonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into responding (CD19-R) and non-responding (CD19-N) sub-populations. Engagement of CD19 by anti-CD19 antibody rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA and exhibited distinct morphological features. Both sub-populations reacted to IgM stimulation in a similar manner and exhibited similar levels of Akt phosphorylation, pointing to functional signaling divergence within the B-cell receptor. CD19 unresponsiveness was partially reversible, where CD19-N cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19-signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow-derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with more than 18.5% of CD19-R cell fraction had a shorter median time to treatment compared to patients with less than 18.5% of CD19-R cell fraction. Conclusions: Divergence in CD19-mediated signaling unfolds both inter-patient and intra-clonal diversity in CLL. This signaling diversity is associated with physiological implications including the location of the cells and disease progression. Disclosures: No relevant conflicts of interest to declare.

Role of T Cell-Derived IL-21 in the Proliferation of Chronic Lymphocytic Leukemia Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3871-3871
Author(s):  
Maria F. Pascutti ◽  
Jacqueline M. Tromp ◽  
Margot Jak ◽  
Ingrid A.M. Derks ◽  
Rene A.W. van Lier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
T Cells ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Activated T Cells ◽  
The One ◽  
Blocking Antibodies

Abstract Abstract 3871 Introduction: Lymph nodes (LN) from chronic lymphocytic leukaemia (CLL) patients contain characteristic proliferation centres, which are interspersed with CD154+ CD4+ T cells. We have previously shown that in vitro stimulation of peripheral blood (PB) CLL cells with CD154-expressing fibroblasts (3T40L) results in an apoptotic profile similar to the one found in LN (Smit et al, Blood 2007 Feb 15;109(4):1660; Kater et al, Br J Haematol 2004;127(4):404). However this stimulus fails to induce proliferation of CLL cells. In fact, the signals involved in CLL proliferation in vivo remain largely unknown. It has recently been described that IL-21 which is produced by activated T cells, has an essential role in activation and proliferation of normal B cells. The aim of this work was to analyze the contribution of IL-21 to the proliferation of CLL cells, both in vitro and in vivo. Results: We stimulated CLL cells with IL-21 in the presence or absence of 3T40L cells and assessed proliferation 5 days later. We observed an increase in the proliferation of CLL cells after the combined stimulation with CD40L and IL-21. In this setting, CLL cells divided once or twice. However, when fresh 3T40L cells and IL-21 were provided every 3–4 days, CLL cells could proliferate passed the fifth division. To analyze the contribution of IL-21 to proliferation in an in vitro setting better resembling the in vivo situation, we then studied the interaction between CLL cells and autologous activated T cells. CLL cells were positively selected from PB and cultured with autologous T cells, activated with CD3/CD28 antibodies (Tact), in the presence/absence of blocking antibodies against CD40L or IL-21 receptor (IL-21R). Proliferation was assessed 2 days later. Co-culture with Tact led to a CD40L- and IL-21-dependent increase in Ki67+CLL cells. Next, we assessed the gene expression profile of CLL cells stimulated with CD40L and/or IL-21 by microarray analysis. CLL cells were stimulated overnight with medium, 3T40L cells, IL-21 or the combination, and then RNA was obtained and analyzed with Affimetrix U133 2.0 microarrays. In CD40L-stimulated cells more than 30 genes were up-regulated by IL-21 (fold induction>4; p<0.005), among which there were components of the JAK-STAT pathway like STAT3, and molecules related to cell proliferation like BCL3 and GS02. This information will allow us to generate an IL-21 signalling signature related to CLL cell proliferation that we will use to interrogate gene expression changes in CLL cells from LN samples. Finally, we wished to ascertain whether IL-21 is being produced in vivo in CLL. For this, we performed IHC stainings on paraffin LN samples from untreated patients. We were able to observe IL-21 production by large cells, scattered among small lymphocytes, which are currently being characterized. Conclusion: Our results indicate that IL-21 might play a role in the proliferation of CLL cells in vivo. This is not only important for understanding the biology of CLL but might also open new venues to treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Molecular Basis of Long First Remissions in Normal Karyotype AML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3827-3827
Author(s):  
Francesca Ferraro ◽  
Christopher A Miller ◽  
Amy Abdalla ◽  
Nichole Helton ◽  
Nathan Salomonis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
High Dose ◽  
Intermediate Risk ◽  
The Mean ◽  
Cebpa Mutations

Currently, it is not clear why some patients with acute myeloid leukemia (AML) can be "cured" with chemotherapy alone; are they living with small amounts of disease that is held in check by immunologic (or other) mechanisms, or is their disease really eradicated? The percentage of cytogenetically normal AML patients who have long (>5 years) first remissions (LFRs) after chemotherapy alone is low (about 9.1% in patients <60 years and 1.6% in >60 years1). For this reason, most intermediate risk patients are offered allogeneic transplantation to decrease their risk for relapse. To better understand mechanisms of chemotherapy sensitivity in AML, we performed an analysis of the mutation landscape and persistence, using samples from 8 normal karyotype LFR patients (without CEBPA mutations) who received standard "7+3" induction and high dose cytarabine consolidation as their only therapy. The mean age at diagnosis was 43.5 years, and the mean follow up in first remission is 7.6 years; none of these patients has relapsed to date. For each case, we performed enhanced exome sequencing at diagnosis (235x coverage of the entire exome, and ~1008x coverage of recurrently mutated AML genes). Each case had at least one documented AML driver mutation, with a median of 29 somatic mutations in the exome space. We created probes for 225 mutations (mean 28 per case), and performed error-corrected sequencing (Haloplex) for all available remission samples. The mean depth of Haloplex coverage was 1607x, and each sample had at least one AML-specific mutation assayed, with a sensitivity of 1 cell in 1,750 (0.06%). 7/8 patients demonstrated complete clearance of all mutations in all remission samples tested, which was confirmed with digital droplet PCR for 5 cases, with a sensitivity of detection of 1 cell in 100,000. In one case, we detected a persistent ancestral clone harboring DNMT3AR882H, which can be associated with long first remissions for some patients2. Strikingly, the founding clone in all 8 cases had one or more somatic mutations in genes known to drive cell proliferation (e.g. MYC, FLT3, NRAS, PTPN11, Figure 1 top panel). These are usually subclonal mutations that occur late during leukemic progression, suggesting that the presence of a "proliferative hit" in the founding clone might be important for chemotherapy clearance of all the AML cells in a given patient. To support this hypothesis, we analyzed the mutational clearance of 82 AML cases with paired diagnosis and day 30 post-chemotherapy bone marrow samples. We observed that, whether present in the founding clone or in subclones, mutations in MYC, CEBPA, FLT3, NRAS, and PTPN11 cleared after induction chemotherapy in all samples, while other mutations were often persistent at day 30 (e.g. DNMT3A, IDH1, IDH2, NPM1, TET2; Figure 1 bottom panel). Compared to other published sequencing studies of AML, MYC and NRAS mutations were significantly enriched in this small cohort (MYC p= 0.002, and NRAS p= 0.034), with MYC enrichment being particularly striking (37.5% versus 1.8%). All MYC mutations were canonical single base substitutions occurring in the highly conserved MYC Box 2 domain at the N-terminus of MYC (p.P74Q or p.T73N). Overexpression of MYCP74Q in murine hematopoietic progenitors prolonged MYC half life (89 min vs. 44 min for wild type), and enhanced cytarabine sensitivity at all concentrations tested (range 10-1000 nM, p=0.0003), both in vitro and in a MYC-driven leukemia model in vivo. MYC expression measured with flow cytometry in the blasts of the LFR samples was significantly higher (p=0.045) compared to unfavorable risk (complex karyotype) or other intermediate risk categories, but similar to good risk AML (biallelic CEBPA mutations, core binding factor fusion-associated AML, and AML with isolated NPMc), suggesting that activation of the MYC pathway may represent a shared feature of chemosensitive patients. Taken together, these data suggest that some intermediate patients who are effectively "cured" with chemotherapy alone may not have persistent subclinical disease, nor retained ancestral clones that could potentially contribute to relapse. Importantly, these patients often have mutations driving cell proliferation in the founding clone, indicating that the presence of specific mutations in all malignant cells may be critical for complete AML cell clearance with chemotherapy. 1. Blood Adv. 2018 Jul 10; 2(13): 1645-1650 2. N Engl J Med 2018; 378:1189-1199 Disclosures No relevant conflicts of interest to declare.

scholarly journals A Novel Type V CRISPR System with Potential for Genome Editing in the Liver

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1862-1862
Author(s):  
Gregory J. Cost ◽  
Morayma Temoche-Diaz ◽  
Janet Mei ◽  
Cristina N. Butterfield ◽  
Christopher T. Brown ◽  
...  
Keyword(s):  
Amino Acid ◽  
Genome Editing ◽  
Mammalian Cells ◽  
Conflicts Of Interest ◽  
Attractive Alternative ◽  
Vitro Assay ◽  
Crispr System ◽  
Type V

Abstract RNA guided CRISPR genome editing systems can make specific changes to the genomes of mammalian cells and have the potential to treat a range of diseases including those that can be addressed by editing hepatocytes. Attempts to edit the liver in vivo have relied almost exclusively on the Cas9 nucleases derived from the bacteria S treptococcus pyogenes or Staphylococcus aureus to which humans are commonly exposed. Pre-existing immunity to both these proteins has been reported in humans which raises concerns about their in vivo application. In silico analysis of a large metagenomics database followed by testing in mammalian cells in culture identified MG29-1, a novel CRISPR system which is a member of the Type V family but exhibits only 41 % amino acid identity to Francisella tularensis Cas12a/cpf1. MG29-1 is a 1280 amino acid RNA programmable nuclease that utilizes a single guide RNA comprised of a 22 nucleotide (nt) constant region and a 20 to 25 nt spacer, recognizes the PAM KTTN (predicted frequency 1 in 16 bp) and generates staggered cuts. MG29-1 was derived from a sample taken from a hydrothermal vent and it is therefore unlikely that humans will have developed pre-existing immunity to this protein. A screen for sgRNA targeting serum albumin in the mouse liver cell line Hepa1-6 identified 6 guides that generated more than 80% INDELS. The MG29-1 system was optimized for in vivo delivery by screening chemical modifications to the guide that improve stability in mammalian cell lysates while retaining or improving editing activity. Two lead guide chemistries were evaluated in mice using MG29-1 mRNA and sgRNA packaged in lipid nanoparticles (LNP). Three days after a single IV administration on-target editing was evaluated in the liver by Sanger sequencing. The sgRNA that was the most stable in the in vitro assay generated INDELS that ranged from 20 to 25% while a sgRNA with lower in vitro stability failed to generate detectable INDELs. The short sgRNA and small protein size compared to spCas9 makes MG29-1 an attractive alternative to spCas9 for in vivo editing applications. Evaluation of the potential of MG29-1 to perform gene knockouts and gene additions via non-homologous end joining is ongoing. Disclosures No relevant conflicts of interest to declare.

scholarly journals KIF23 Promotes Gastric Cancer by Stimulating Cell Proliferation

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-Long Li ◽  
Ya-Ming Ji ◽  
Rui Song ◽  
Xiao-Ning Li ◽  
Lan-Shuan Guo
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Malignant Tumors ◽  
Vital Role ◽  
Gastric Cancer Cells ◽  
Vitro Assay ◽  
Multiple Tumor ◽  
Axon Elongation ◽  
Underlying Mechanisms

Gastric cancer (GC) is one of the most aggressive malignant tumors with low early diagnosis and high metastasis. Despite progress in treatment, to combat this disease, a better understanding of the underlying mechanisms and novel therapeutic targets is needed. KIF23, which belongs to the KIF family, plays a vital role in various cell processes, such as cytoplasm separation and axon elongation. Nowadays, KIF23 has been found to be highly expressed in multiple tumor tissues and cells, suggesting a potential link between KIF23 and tumorigenesis. Herein, we reported that KIF23 expression was correlated with poor prognosis of gastric cancer and found an association between KIF23 and pTNM stage. An in vitro assay proved that the proliferation of gastric cancer cells was significantly inhibited, which is caused by KIF23 depletion. Additionally, knockdown of KIF23 resulted in a marked inhibition of cell proliferation of gastric cancer in mice, with significant downregulation of Ki67 and PCNA expression. In conclusion, these data indicate that KIF23 is a potential therapeutic target for gastric cancer treatment.

scholarly journals High efficacy of a dimeticone-based pediculicide following a brief application: in vitro assays and randomized controlled investigator-blinded clinical trial

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jorg Heukelbach ◽  
Doerte Wolf ◽  
John Marshall Clark ◽  
Hans Dautel ◽  
Kristina Roeschmann
Keyword(s):  
Clinical Trial ◽  
Test Group ◽  
Head Lice ◽  
Ovicidal Activity ◽  
Vitro Assay ◽  
Test Product ◽  
Randomized Controlled ◽  
Development Of Resistance ◽  
Reduced Risk

Abstract Background Increasing resistance of head lice against neurotoxic agents and safety concerns have led to the search for treatment alternatives. Dimeticones with a physical mode of action are safe, and bear a reduced risk for the development of resistance. Methods We performed in vitro bioassays to assess pediculicidal and ovicidal activities of a new dimeticone-based product, and a randomized controlled clinical trial to assess efficacy, following 10 min application. Of 153 individuals screened, 100 participants with active head louse infestations were randomly assigned to treatment with either a dimeticone-based test product, or a 0.5% permethrin-based reference product (50 participants per group). Participants received two topical applications of either the test (10 min) or reference products (45 min) at days 0 and 7 or 8. Outcome measures included the efficacies of treatment and their safety, as well as global and local tolerability at baseline, and days 1, 7, and 10. Results After 10 min exposure, all lice treated with the dimeticone test product were classified as non-viable in the in vitro assay. Ovicidal activity after treatment of eggs with the dimeticone test product was 96.8%. In the clinical trial, 96 patients completed all study visits. In the full analysis set (FAS) population, on day 1 after one application, 98% of patients were cured in the test group, as compared to 84% cured in the reference group. All participants in both groups were free of head lice on day 10, following two applications (100% cure rate). In total, 42 adverse events (AEs) in 23 patients of both treatment groups were recorded, with the majority of AEs classified as mild. Conclusions We have shown a high level of pediculicidal and ovicidal activity, and clinical efficacy and safety, of a brief application of a new dimeticone-based product. The short application time and reduced risk for the development of resistance are key drivers for improved patients’ compliance. Trial registration EU Clinical Trials Register EudraCT 2016–004635-20. Registered 14 November 2016.

scholarly journals Kava constituents exert selective anticancer effects in oral squamous cell carcinoma cells in vitro

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Antonio Celentano ◽  
Callisthenis Yiannis ◽  
Rita Paolini ◽  
Pangzhen Zhang ◽  
Camile S. Farah ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Squamous Cell Carcinoma ◽  
Cell Migration ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
Vitro Assay ◽  
Anticancer Effects

Abstract Kava is a beverage made from the ground roots of the plant Piper Methysticum. Active compounds of Kava have previously been demonstrated to exert an antiproliferative effect through cell cycle arrest and promotion of apoptosis. Our aim was to investigate the in vitro effects of the main constituents derived from Kava on oral squamous cell carcinoma (OSCC) activity. Gas chromatography mass spectrometry (GCMS) was used to characterise the main constituents of two Kava preparations. Cell proliferation was assessed in two human OSCC cell lines (H400 and BICR56) and in normal oral keratinocytes (OKF6) treated with the identified Kava constituents, namely Flavokawain A (FKA), Flavokawain B (FKB), yangonin, kavain and methysticin using an MTS in vitro assay. Cell migration at 16 h was assessed using a Transwell migration assay. Cell invasion was measured at 22 h using a Matrigel assay. Cell adhesion was assessed at 90 min with a Cytoselect Adhesion assay. The two Kava preparations contained substantially different concentrations of the main chemical constituents. Treatment of malignant and normal oral keratinocyte cell lines with three of the identified constituents, 10 μg/ml FKA, 2.5 μg/ml FKB and 10 μg/ml yangonin, showed a significant reduction in cell proliferation in both H400 and BICR56 cancer cell lines but not in normal OKF6 cells. Remarkably, the same Kava constituents induced a significant reduction of OSCC cell migration and invasion. We have demonstrated, for the first time, that Kava constituents, FKA, FKB and yangonin have potential anticancer effects on OSCC. This highlights an avenue for further research of Kava constituents in the development of future cancer therapies to prevent and treat OSCC.

Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 96-103 ◽  
Author(s):  
Jan A. Burger
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Disease Progression ◽  
Drug Testing ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
In Vivo Models

Abstract Intrinsic factors such as genetic lesions, anti-apoptotic proteins, and aberrant signaling networks within leukemia cells have long been the main focus of chronic lymphocytic leukemia (CLL) research. However, over the past decade, it became increasingly clear that external signals from the leukemia microenvironment make pivotal contributions to disease progression in CLL and other B-cell malignancies. Consequently, increasing emphasis is now placed on exploring and targeting the CLL microenvironment. This review highlights critical cellular and molecular pathways of CLL-microenvironment cross-talk. In vitro and in vivo models for studying the CLL microenvironment are discussed, along with their use in searching for therapeutic targets and in drug testing. Clinically, CXCR4 antagonists and small-molecule antagonists of B cell receptor (BCR)-associated kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], and PI3Kδ) are the most advanced drugs for targeting specific interactions between CLL cells and the miocroenvironment. Preclinical and first clinical evidence suggests that high-risk CLL patients can particularly benefit from these alternative agents. These findings indicate that interplay between leukemia-inherent and environmental factors, nature and nurture determines disease progression in CLL.

scholarly journals Effects of chlorambucil and therapeutic decision in initial forms of chronic lymphocytic leukemia (stage A): results of a randomized clinical trial on 612 patients. The French Cooperative Group on Chronic Lymphocytic Leukemia

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1414-1421 ◽  
Keyword(s):  
Clinical Trial ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Randomized Clinical Trial ◽  
Survival Rates ◽  
Harmful Effect ◽  
Good Prognosis ◽  
Untreated Group ◽  
Lymphocytic Leukemia ◽  
Cooperative Group

Abstract In 1980, the French Cooperative Group on Chronic Lymphocytic Leukemia started a randomized clinical trial in which 612 good prognosis patients (stage A) received either no treatment (309 patients) or an indefinite course of chlorambucil at the daily dose of 0.1 mg/kg (303 patients). Overall survival appeared to be better in the untreated group (50 deceased patients compared with 62 in the chlorambucil group), but the difference was not significant (P = .21) even after adjusting for both prognostic and imbalanced factors (P = .09). The crude 5-year survival rates were 82% in the untreated group and 75% in the chlorambucil group. The action of chlorambucil appeared to be a complex phenomenon associating beneficial effects consisting in slowing down disease progression to stage B or C (P less than .01), and favoring disease remission with harmful effects given by a short survival after disease progression to stage B or C in the chlorambucil group and an increased incidence of epithelial cancers (33 v 19), as well as an excess of epithelial cancer deaths (13 v 3), in the chlorambucil group. As these results suggested an overall harmful effect of chlorambucil, we tried to define, within stage A patients, a group of patients with a low probability of disease progression. We showed that stage A patients with hemoglobin greater than or equal to 120 g/L and lymphocyte count less than 30 x 10(9)/L had a survival that was not significantly different (P = .46) from that of the age- and sex- matched French population. These patients, accounting for about 50% of all chronic lymphocytic leukemia patients, should not be treated unless disease progression is observed.

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