scholarly journals Single Agent Polysaccharopeptide Delays Metastases and Improves Survival in Naturally Occurring Hemangiosarcoma

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Dorothy Cimino Brown ◽  
Jennifer Reetz
Keyword(s):  
Cancer Patients ◽  
Large Scale ◽  
Single Agent ◽  
Treatment Strategies ◽  
World Health ◽  
High Dose ◽  
Survival Times ◽  
Double Blind ◽  
Naturally Occurring

The 2008 World Health Organization World Cancer Report describes global cancer incidence soaring with many patients living in countries that lack resources for cancer control. Alternative treatment strategies that can reduce the global disease burden at manageable costs must be developed. Polysaccharopeptide (PSP) is the bioactive agent from the mushroomCoriolus versicolor. Studies indicate PSP has in vitro antitumor activities and inhibits the growth of induced tumors in animal models. Clear evidence of clinically relevant benefits of PSP in cancer patients, however, is lacking. The investment of resources required to complete large-scale, randomized controlled trials of PSP in cancer patients is more easily justified if antitumor and survival benefits are documented in a complex animal model of a naturally occurring cancer that parallels human disease. Because of its high metastatic rate and vascular origin, canine hemangiosarcoma is used for investigations in antimetastatic and antiangiogenic therapies. In this double-blind randomized multidose pilot study, high-dose PSP significantly delayed the progression of metastases and afforded the longest survival times reported in canine hemangiosarcoma. These data suggest that, for those cancer patients for whom advanced treatments are not accessible, PSP as a single agent might offer significant improvements in morbidity and mortality.

scholarly journals Human peripheral blood hematopoietic progenitors are optimal targets of retroviral-mediated gene transfer

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1418-1422 ◽  
Author(s):  
M Bregni ◽  
M Magni ◽  
S Siena ◽  
M Di Nicola ◽  
G Bonadonna ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Cancer Patients ◽  
Resistance Gene ◽  
Peripheral Blood ◽  
Large Scale ◽  
Human Peripheral Blood ◽  
High Dose ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem

Abstract Hematopoietic progenitor cells circulate in the peripheral blood (PB) of cancer patients during the recovery phase that follows treatment with high-dose cyclophosphamide followed by hematopoietic growth factor infusion. We report that when PB progenitors were exposed in vitro to filtered supernatant from cell line PA317-N2, producing amphotropic helper-free N2 vector at conventional titers, successful retroviral- mediated transfer of neomycin resistance gene was documented by polymerase chain reaction in 93% of day 14 myelomonocytic colonies. Under the same conditions, gene transfer was achieved in 22% of steady- state bone marrow-derived myelomonocytic colonies. Neo-resistance gene transfer was documented also in a CD34+/cyclophosphamide-resistant precursor to granulocyte-macrophage colonies, an undifferentiated progenitor close to the hematopoietic stem cell. Neither cocultivation with vector-producing cells nor high vector titer were stringent requisites for efficient gene transfer. The large-scale availability of PB hematopoietic progenitors in cancer patients, together with the high gene transfer rate achieved under safe and clinically feasible conditions, support an optimal approach for gene transfer procedures into the human hematopoietic system.

scholarly journals Human peripheral blood hematopoietic progenitors are optimal targets of retroviral-mediated gene transfer

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1418-1422 ◽  
Author(s):  
M Bregni ◽  
M Magni ◽  
S Siena ◽  
M Di Nicola ◽  
G Bonadonna ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Cancer Patients ◽  
Resistance Gene ◽  
Peripheral Blood ◽  
Large Scale ◽  
Human Peripheral Blood ◽  
High Dose ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem

Hematopoietic progenitor cells circulate in the peripheral blood (PB) of cancer patients during the recovery phase that follows treatment with high-dose cyclophosphamide followed by hematopoietic growth factor infusion. We report that when PB progenitors were exposed in vitro to filtered supernatant from cell line PA317-N2, producing amphotropic helper-free N2 vector at conventional titers, successful retroviral- mediated transfer of neomycin resistance gene was documented by polymerase chain reaction in 93% of day 14 myelomonocytic colonies. Under the same conditions, gene transfer was achieved in 22% of steady- state bone marrow-derived myelomonocytic colonies. Neo-resistance gene transfer was documented also in a CD34+/cyclophosphamide-resistant precursor to granulocyte-macrophage colonies, an undifferentiated progenitor close to the hematopoietic stem cell. Neither cocultivation with vector-producing cells nor high vector titer were stringent requisites for efficient gene transfer. The large-scale availability of PB hematopoietic progenitors in cancer patients, together with the high gene transfer rate achieved under safe and clinically feasible conditions, support an optimal approach for gene transfer procedures into the human hematopoietic system.

scholarly journals BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽  
2018 ◽  
Vol 3 (6) ◽  
pp. e000387 ◽  
Author(s):  
Chiara Tarantelli ◽  
Elena Bernasconi ◽  
Eugenio Gaudio ◽  
Luciano Cascione ◽  
Valentina Restelli ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Antitumour Activity ◽  
Single Agent ◽  
Treatment Strategies ◽  
Bet Inhibitor ◽  
Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

scholarly journals A Single Administration of AZP-3601, a Novel, Long-Acting PTH Analog, Induces a Significant and Sustained Calcemic Response: Preliminary Data From a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A254-A254
Author(s):  
Soraya Allas ◽  
Michel Ovize ◽  
Michael D Culler ◽  
Clarisse Geraul ◽  
Jeroen van de Wetering ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Clinical Symptoms ◽  
Phase 1 ◽  
High Dose ◽  
Single Administration ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Healthy Humans ◽  
Dose Dependent

Abstract Hypoparathyroidism is a rare disease characterized by a deficiency in parathyroid hormone (PTH) that results in hypocalcemia and hyperphosphatemia. Current treatment approaches, including high dose oral calcium and active vitamin D, as well as recombinant human PTH (1–84), do not provide adequate or consistent control of either serum calcium or clinical symptoms over a full 24-hour period. AZP-3601 is a novel 36 amino-acid PTH analog that has been designed to potently bind to the R0 conformation of the PTH1 receptor, which results in prolonged signaling responses in vitro and prolonged calcemic responses in animals despite having a short circulating half-life. A Phase 1 double-blind, placebo-controlled, single and multiple ascending dose study is being conducted to evaluate the safety, tolerability and pharmacodynamics of AZP-3601 in healthy adults. Here we report data from the first cohorts of the single ascending dose portion of the study. Sequential cohorts of 4 (cohort 1) to 8 (cohort 2 to 4) healthy male subjects aged 18–60 years, with a body mass index of 19–28 kg/m2, were assigned to receive 5, 10, 20 or 40μg of AZP-3601 or placebo at a ratio of 3:1. The study drug was administered in the morning by subcutaneous injection in the abdominal wall and was well tolerated with no remarkable adverse events. As compared with placebo controls, AZP-3601 treatment produced a clear, dose-dependent increase in mean albumin-adjusted serum calcium values from baseline. The normal physiological diurnal variation of albumin-adjusted serum calcium was gradually attenuated with 5 and 10μg AZP-3601, and was completely eliminated with 20μg. With the dose of 40μg AZP-3601, mean albumin-adjusted serum calcium values were significantly increased but stayed within normal laboratory range and remained elevated through at least 24 hours post-administration. We observed a dose-dependent decrease in mean endogenous serum PTH that was significantly correlated with the concomitant increase in mean serum calcium. These data provide initial evidence of the pharmacodynamic effect of AZP-3601 in healthy humans characterized by a sustained calcemic response for at least 24 hours following a single administration.

scholarly journals Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

2020 ◽  
Vol 117 (48) ◽  
pp. 30670-30678
Author(s):  
Olivera Grbovic-Huezo ◽  
Kenneth L. Pitter ◽  
Nicolas Lecomte ◽  
Joseph Saglimbeni ◽  
Gokce Askan ◽  
...  
Keyword(s):  
Large Scale ◽  
Single Agent ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
In Vivo Model ◽  
Cancer Therapies ◽  
Hsp90 Inhibition ◽  
Dismal Prognosis

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies.

Reduced thromboembolic events with DN-101 (high-dose calcitriol) treatment of androgen-independent prostate cancer: Hypothesis for a new class of anticoagulants

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4505-4505 ◽  
Author(s):  
P. M. Venner ◽  
C. Ryan ◽  
D. P. Petrylak ◽  
G. S. Chatta ◽  
J. Ruether ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Active Form ◽  
Coagulation Cascade ◽  
Controlled Study ◽  
High Dose ◽  
Thromboembolic Events ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Androgen Independent

4505 Background: Thromboembolic events (TEs) occur at an increased rate in patients with advanced malignancies including androgen-independent prostate cancer (AIPC). DN-101, a new high-dose oral formulation of calcitriol (1,25-dihydroxycholecalciferol), is the active form of Vitamin D and the natural ligand for the nuclear receptor VDR. Calcitriol upregulates thrombomodulin, a natural anticoagulant, and downregulates tissue factor, a procoagulant both in vitro and in vivo. Further, VDR knockout mice demonstrate increased susceptibility to thrombosis. ASCENT is a double-blind, placebo-controlled study in 250 men with metastatic AIPC. Efficacy results have been previously reported (ASCO, 2005). Methods: 250 patients were randomized 1:1 to docetaxel 36 mg/m2 plus 45 μg DN-101 weekly or to the same docetaxel regimen plus placebo. In this exploratory analysis the incidence of TE (defined as deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), cerebrovascular accident (CVA) and arterial thrombosis (AT)) in the two study groups was compared using the Fisher’s exact test. Results: There were fewer patients with serious adverse events (SAEs) in the DN-101 group than in the placebo group (27 % vs. 41%). As shown in the table , DN-101 treated patients experienced fewer TEs including fewer TE SAEs, Grade 3 or 4 TEs and all grade TEs. No imbalance in baseline use of anticoagulants was observed. Conclusions: The well-described effects of calcitriol on protein components of the coagulation cascade provide a biologic basis for the observed reduction in thromboembolic events in the DN-101 treated patients. This hypothesis should be tested prospectively in future studies of DN-101. [Table: see text] [Table: see text]

Effect of short course, high-dose valproic acid on proliferation in breast adenocarcinomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13522-e13522
Author(s):  
Adam Louis Cohen ◽  
Rachel Factor ◽  
Matthias Schabel ◽  
Andrea Bild ◽  
Theresa Louise Werner
Keyword(s):  
Valproic Acid ◽  
Standard Dose ◽  
Single Agent ◽  
In Vivo Studies ◽  
Breast Adenocarcinoma ◽  
High Dose ◽  
Breast Cancers ◽  
Dce Mri ◽  
Mib 1

e13522 Background: Our in vitro and in vivo studies showed that single agent valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is effective in a subset of breast cancers. Whether VPA is effective as a single agent and what the optimal dosing would be are unknown. Methods: In an ongoing IRB-approved, window-of-opportunity study testing a genomic predictor of sensitivity to VPA (NCT01007695), we performed biopsies and DCE-MRI on women before and after seven days of escalating doses of VPA on untreated women with breast adenocarcinoma with an intact breast tumor. Within patient dose-escalation was done with a goal dose of 50 mg/kg. Proliferation was assessed with MIB-1 immunohistochemistry. Only correlative secondary endpoints are presented here. Results: Sixteen women have completed treatment and are evaluable. Total and free VPA levels on the last day of treatment averaged 136 µg/ml (range 15-242) and 30 µg/ml (range 1-90), respectively. Proliferation rate by MIB-1 decreased by and average of -7.25% (range +4% to -45%, p=0.04). The change in proliferation did not correlated with VPA levels, although only one of four women with VPA levels less than 100 µg/ml had a decrease in proliferation, compared to five of twelve women with VPA levels greater than 100 µg/ml. Four women had MIB-1 decreases of 10% or greater. Two women have had post-treatment biopsies with fibrosis similar to that seen with chemotherapy treatment effect. DCE-MRI parameters, including ktrans, vp, and kep, did not change significantly with VPA treatment or correlate with VPA levels. Conclusions: VPA as a single agent can reduce proliferation in a subset of women with breast cancers. Higher VPA levels are needed than those achieved at standard dose levels, but VPA levels by themselves do not predict effect. Other monitoring parameters, such as peripheral blood histone acetylation changes, or other predictors of benefit are needed. Clinical trial information: NCT01007695.

scholarly journals Immunogenicity and safety of a third dose, and immune persistence of CoronaVac vaccine in healthy adults aged 18-59 years: interim results from a double-blind, randomized, placebo-controlled phase 2 clinical trial

2021 ◽  
Author(s):  
Hongxing Pan ◽  
Qianhui Wu ◽  
Gang Zeng ◽  
Juan Yang ◽  
Deyu Jiang ◽  
...  
Keyword(s):  
Large Scale ◽  
Dose Group ◽  
Geometric Mean ◽  
Development Program ◽  
Neutralizing Antibody ◽  
Immune Memory ◽  
High Dose ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
Double Blind

Background Large-scale vaccination is being implemented globally with CoronaVac, an inactivated vaccine against coronavirus disease 2019 (COVID-19). Immunogenicity and safety profiles of homologous two-dose schedules have been published. We report interim results of immune persistence, and the immunogenicity and safety of a third dose of CoronaVac. Methods In this ongoing, placebo-controlled, double-blind phase 2 trial in 18-to-59-year-olds, we randomly assigned subjects, 1:1:1:1, to one of four schedules to receive a third dose, 28 days or 6 months after two two-dose regimens (14-day or 28-day apart): schedule 1: days 0, 14, 42; schedule 2: days 0, 14, 194; schedule 3: days 0, 28, 56; schedule 4: days 0, 28, 208. For each schedule, participants were randomly assigned to either a medium-dose group (3 μg per 0.5 mL of aluminum hydroxide diluent per dose), a high-dose group (6 μg), or a placebo group (2:2:1). The primary outcome was geometric mean titers (GMTs) of neutralizing antibody to live SARS-CoV-2. Results Overall, 540 participants received a third dose. In the 3 μg group, neutralizing antibody titers induced by the first two doses declined after 6-8 months to below the seropositive cutoff (GMT: 4.1 [95%CI 3.3-5.2] for Schedule 2 and 6.7 [95%CI 5.2-8.6] for Schedule 4). When a third dose was given 6-8 months after a second dose, GMTs assessed 14 days later increased to 137.9 [95%CI 99.9-190.4] for Schedule 2, and 143.1 [95%CI 110.8-184.7] for Schedule 4, approximately 3-fold above Schedule 1 and Schedule 3 GMTs after third doses. Similar patterns were observed for the 6 μg group. The severity of solicited local and systemic adverse reactions reported within 28 days after the third dose were grade 1 to grade 2 in all vaccination cohorts. None of the fourteen serious adverse events were considered to be related to vaccination. Conclusions A third dose of CoronaVac administered 6 or more months after a second dose effectively recalled specific immune response to SARS-CoV-2, resulting in a remarkable increase in antibody levels, and indicating that a two-dose schedule generates good immune memory. Optimizing the timing of a booster dose should take into account immunogenicity, vaccine efficacy/effectiveness, local epidemic situation, infection risk, and vaccine supply. (Funded by the National Key Research and Development Program, Beijing Science and Technology Program and National Science Fund for Distinguished Young Scholars; ClinicalTrials.gov number, NCT04352608.)

Gene expression profiling (GEP) of cd 138-purified plasma cells (pc) in previously treated multiple myeloma (PTMM): Validating prognostic models developed in newly diagnosed MM (NDMM)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8598-8598
Author(s):  
Y. Alsayed ◽  
J. Haessler ◽  
B. Barlogie ◽  
J. Crowley ◽  
J. Shaughnessy
Keyword(s):  
High Risk ◽  
Plasma Cells ◽  
Clonal Evolution ◽  
Single Agent ◽  
Treatment Strategies ◽  
Prognostic Models ◽  
High Dose ◽  
Molecular Subgroup ◽  
Chromosome 1Q ◽  
High Dose Dexamethasone

8598 Background: We have previously reported on the strong discriminatory power in NDMM of GEP-derived 70-gene risk in CD138-purified plasma-cells developed in 351 patients enrolled in TT2 and validated in 441 patients enrolled in two TT3 trials and in PTMM treated with single agent high-dose dexamethasone or bortezomib. Here we report on the overall survival outcomes in 137 patients with PTMM. Methods: Treatment regimens included further autotransplantation and novel agent combinations. The purpose of the investigation was to determine whether PTMM OS was also governed by GEP features, such as high-risk (HR) score, proliferation score (PS), proliferation (PR) molecular subgroup, gain/amplification of chromosome 1q (amp1q) and deletion of the short arm (del1p) and TP53 deletion. Results: Compared with NDMM, PTMM was characterized by greater proportions with HR (32% v 16%, p<0.001), PS (20% v 10%, p=0.002) and PR (24% v 11%, p < 0.001); no difference was observed for TP53 deletion (21% v 30%, p=0.11); amp1q/del1p was more common in PTMM (17% v 9%, p=0.01). OS was 60% at 8yr in NDMM compared to a median of only 2.4yr in PTMM. According to HR, 4-yr OS estimates were 80% for LR v 37% for HR in NDMM (p<0.0001) and 52% for LR v 24% for HR in PTMM (p<0.01). On multivariate analysis of both standard prognostic factors and GEP HR, OS in PTMM was adversely affected by HR status (HR=2.00, p=0.047) and albumin <3.5g/dL (HR=2.66, P=0.013), accounting for a cumulative R2 value of 20%. Conclusions: GEP-derived high-risk features are more prevalent in PTMM relative to NDMM in terms of HR, PS, PR and amp1q/del1p status. As in NDMM, HR status confers poor OS in PTMM. Consistent with serial sampling where LR to HR transformation routinely occurs, these data support the concept that HR in PTMM is derived from clonal evolution. Treatment strategies that presume the existence of underlying HR cells even in LR disease, should be pursued. [Table: see text]

AT 101, an Inhibitor of Bcl-2 Family Members Is Cytotoxic to a Heterogeneous Group of CLL Samples and Synergistic with Rituximab.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2979-2979 ◽  
Author(s):  
Danelle F. James ◽  
Carlos E. Prada ◽  
Januario E. Castro ◽  
Thomas J. Kipps
Keyword(s):  
Cytochrome C ◽  
Single Agent ◽  
Constitutive Expression ◽  
High Dose ◽  
Dependent Manner ◽  
Caspase Activation ◽  
Response To Chemotherapy ◽  
Synergistic Cytotoxicity ◽  
Apoptotic Proteins

Abstract Bcl-2 family proteins include both pro-survival and pro-apoptotic factors. The balance of these regulatory proteins determines a cell’s threshold for death. Bcl-2, Bcl-XL, and Mcl-1 are structurally related anti-apoptotic proteins of the Bcl-2 family. Constitutive expression of Bcl-2 is characteristic of CLL and has been implicated in the leukemia’s pro-survival tendency. In addition, high level expression of Mcl-1 and Bcl-2 have been shown to correlate with important clinical outcomes in CLL such as poor response to chemotherapy and decreased overall survival. Bcl-2 prevents mitochondrial cytochrome c release and inhibits apoptosis through direct regulation of caspases. The BH3-only proteins dimerize and neutralize their pro-survival counterparts via interaction with the BH3 binding grove on the anti-apoptotic proteins. This interaction results in the release of cytochrome c, subsequent caspase activation, and resultant cell death. Gossypol is a naturally occurring product found in cottonseed oil. AT 101, an orally bio-available derivative of gossypol is currently being evaluated in cancer clinical trials. AT 101 is a small molecule that mimics the inhibitory BH3 domain of endogenous antagonists of Bcl-2 negating its cytoprotective role. AT 101 induces apoptosis via caspase activation in cancer cells that over-express Bcl-2 or Bcl-XL, but had no significant cytotoxic effect on normal blood mononuclear cells (Mohammad, 2005). Fluorescence polarization assays demonstrate that AT 101 binds to Bcl-2, BcL-XL, and Mcl-1 with greater affinity than gossypol (Prada,ASH 2005). We hypothesized that inhibiting Bcl-2 and Mcl-1 by AT 101 may allow the CLL cells to enter apoptosis more readily and render them more sensitive to standard CLL therapeutics. We tested 10 different primary CLL patient samples in vitro and found gossypol to be cytotoxic in a dose and time dependent manner. We observed 50% reduction in CLL cell viability at a concentration of 2μM after 48 hours of treatment. Significant cytotoxicity was observed irrespective of ZAP-70 expression or IgVH mutational status. Increased ratios of Bcl-2/Bax and Mcl-1/Bax have been demonstrated in CLL patients who do not respond to rituximab (Bannerji 2003). To examine the ability of gossypol to enhance the cytotoxic effects of rituximab in CLL we evaluated samples from 6 different patients affected with the leukemia in vitro. CLL cells treated with rituximab at 10μg/ml showed no significant decrease in viability compared to untreated cells. When AT 101 was added at 5μM concentrations in combination with rituximab 10μg/ml for twelve hours the average CLL viability was decreased by 67.2% over that of cells treated with rituximab alone (P&lt;0.001 by Bonferroni multiple comparison test) and by 45.3% over cells treated with AT 101 alone (P&lt;0.001). The combined effect of AT 101 and rituximab appears synergistic and is displayed throughout CLL subtypes. In our studies we were unable to reach the IC50 of rituximab on CLL using doses up to 100μg/ml. However, the addition of AT 101 to rituximab 10μg/ml surpassed the IC50 and demonstrated similar cytotoxicity to that of high dose rituximab100μg/ml when used in conjunction with AT 101. Together our results suggest that AT 101 may have therapeutic potential in CLL as a single agent or in concert with other known CLL therapeutics. In particular, AT 101 was found to have synergistic cytotoxicity when combined with rituximab. Currently a phase I clinical trial is underway to evaluate the activity of AT 101 in previously untreated patients with CLL.

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