Need For Better Therapeutic Options Research Articles

Thymidylate Synthase Inhibition with the Novel Fluoropyrimidine FdUMP[10] Is Highly Effective Against Acute Lymphoblastic Leukemia

AbstractAbstract 1505Despite significant improvements in cure rates in pediatric patients, outcomes in adults with acute lymphoblastic leukemia (ALL) remain dismal with an estimated 5-year survival of less than 10% for patients over the age of 60. Compared to children, ALL in adults is characterized by an increased incidence of poor prognostic cytogenetics, lower complete remission rates, and higher relapse rates. Once relapse occurs in adults, the outcome is truly dismal, with a 6% salvage rate with current therapies. Initial treatment of ALL combines essentially all currently used agents, leaving very few therapies once relapse occurs. There is a clear need for better therapeutic options for these patients.5-Fluorouracil (5-FU) is a fluoropyrimidine (FP) prodrug that must first be converted to 5-fluoro-2’-deoxyuridine-5’-O-monophosphate (FdUMP) in order to inhibit thymidylate synthase (TS) and shut down tumor thymidine synthesis. It can also be metabolized to a ribose metabolite that interferes with RNA processing and leads to toxicity in any transcriptionally active cell. The profound GI toxicities of 5-FU and lack of potency against ALL has lead to the abandonment of TS inhibition in the treatment of ALL. In contrast, FdUMP[10] is a oligodeoxynucleotide containing 10 FdUMP moieties linked by phosphodiester bonds. FdUMP[10] has profound activity against preclinical models of acute myeloid leukemia (AML), with minimal toxicities. The human T cell ALL cell line, Jurkat, was extremely sensitive to FdUMP[10], with an IC50of 5.4nM (95% CI 4.609–6.417). We sought to determine the activity of FdUMP[10] against additional preclinical ALL models.In vitro, FdUMP[10] exhibited remarkable activity against the human T and B Cell ALL cell lines, DG75, Molt-4, CCRF-CEM, and SUP-B15 with an average IC50 value of 1.83nM (Range 0.21–4.1nM). In two murine ALL cell lines driven by expression of BCR-ABL, FdUMP[10] exhibited even greater activity, with an average IC50 value of 0.662nM (range 0.125–1.2nM). For comparison we also tested 5-FU and cytarabine in the same assay against DG75, MOLT-4 and a BCR-ABL driven murine line. In all cases FdUMP[10] was the most potent agent and was more than 1000 times more potent than 5-FU despite having only 10 times the FP content. In vivo, FdUMP[10] treatment provided a statistically significant increase in survival in a BCR-ABL driven, syngeneic ALL mouse model (p=0.0002 by log rank test). In a separately derived syngeneic model expressing the T315I variant of BCR-ABL, treatment with FdUMP[10] significantly prolonged survival (p=0.0013).In AML models exposure to FdUMP[10] resulted in apoptosis. To assess if ALL cells undergo a similar apoptotic response we exposed human and mouse ALL cells to FdUMP[10] and assessed for apoptosis induction via propidium iodide (PI) and Annexin V staining. As we found previously in AML models, FdUMP[10] exposure resulted in a robust induction of Annexin V and PI staining consistent with an apoptotic response. The level of apoptosis with FdUMP[10] could not be reproduced by 5-FU even when used at 100 times higher concentration.To determine the effect of FdUMP[10] on thymidylate synthase (TS) activity in ALL, Jurkat cells were exposed to 10nM FdUMP[10] or 100nM 5- FU and TS activity was assayed. We found a profound and prolonged inhibition with FdUMP[10] compared to 5-FU, despite the identical amount of fluoropyrimidine.FdUMP[10] is synergistic with doxorubicin and cytarabine in AML models. To assess whether FdUMP[10] could synergize with targeted therapy in ALL, Baf-3 cells expressing BCR-ABL were exposed to the tyrosine kinase inhibitor nilotinib plus FdUMP[10]. The combination was synergistic, with combinatory index values of 0.7113 to 0.4803. In preliminary data in vivo, the combination of FdUMP[10] and nilotinib resulted in a greater reduction in leukemic burden then nilotinib alone.In summary, FdUMP[10] exhibited remarkable activity against human and murine ALL cells in vitro and in vivo by inducing apoptosis and profound TS inhibition, and showing a synergistic benefit when combined with nilotinib. These data demonstrate that TS is a valid target in ALL cells. This fact combined with previous studies demonstrating a favorable toxicity profile, make FdUMP[10] a promising candidate for treatment of ALL. Disclosures:Pardee:Salzburg Therapuetics: Membership on an entity's Board of Directors or advisory committees. Gmeiner:Salzburg Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Rapid bactericidal action of alpha-mangostin against MRSA as an outcome of membrane targeting

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created the need for better therapeutic options. In this study, five natural xanthones were extracted and purified from the fruit hull of Garcinia mangostana and their antimicrobial properties were investigated. α-Mangostin was identified as the most potent among them against Gram-positive pathogens (MIC=0.78–1.56μg/mL) which included two MRSA isolates. α‐Mangostin also exhibited rapid in vitro bactericidal activity (3-log reduction within 5min). In a multistep (20 passage) resistance selection study using a MRSA isolated from the eye, no resistance against α-mangostin in the strains tested was observed. Biophysical studies using fluorescence probes for membrane potential and permeability, calcein encapsulated large unilamellar vesicles and scanning electron microscopy showed that α‐mangostin rapidly disrupted the integrity of the cytoplasmic membrane leading to loss of intracellular components in a concentration-dependent manner. Molecular dynamic simulations revealed that isoprenyl groups were important to reduce the free energy for the burial of the hydrophobic phenyl ring of α-mangostin into the lipid bilayer of the membrane resulting in membrane breakdown and increased permeability. Thus, we suggest that direct interactions of α-mangostin with the bacterial membrane are responsible for the rapid concentration-dependent membrane disruption and bactericidal action.

Left Ventricular Assist Devices Are Underutilized

Heart failure has become one of the fastest growing cardiovascular diagnoses, with estimates as high as 500 000 new cases per year.1,2 This growth is in part a result of the reductions in death from acute coronary syndromes, increased use of implantable cardioverter defibrillators, and improved survival with most cardiovascular interventions, which have led to this continued increase in the number of patients who develop progressive heart failure (HF). The estimated number of people in the United States with the diagnosis of HF may exceed 7 million, based on the estimated average prevalence of 2.6%,3,4 and a census of >300 million population (Figure 1).5,6 HF is clearly age related,1,–,4 with prevalence as low as 0.5% in those 65 years of age.2 This is an important demographic, because it is estimated that the number of people >65 years of age will double in the next 20 to 30 years.4,–,7 HF is not a homogeneous condition. Based primarily on data from recent hospital registries8,9 and other studies,10 nearly half of all patients have HF with preserved systolic function, and the other half have varying degrees of severity of HF with reduced systolic function. Although the prevalence of HF is higher in males at <70 years of age, overall HF is equally common in men and women. Unfortunately, the average survival of patients with either preserved or reduced systolic function is only 40% at 5 years after diagnosis,10,11 and may be as high as 80% when it reaches a refractory stage.12 One study of 3500 patients in Minnesota suggested that there is …

Primary plasma cell leukemia

Primary plasma cell leukemia (PCL) is a rare plasma cell disorder, and current knowledge regarding survival in this disease is limited to small series of patients. Although there has been significant improvement in the survival of patients with multiple myeloma (MM) over the past few decades, it is not known whether there has been a similar trend for PCL. The authors analyzed the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the characteristics and survival of patients who had PCL compared with those of patients who had MM. Among 291 patients with PCL, the median age was 67 years (range, 19-98 years), the distribution of men and women was nearly equal, and the majority of patients were white (79.4%). The median overall survival (OS) was 4 months and the median disease-specific survival (DSS) was 6 months for patients with PCL; the 1-year, 2-year, and 5-year OS rates were 27.8%, 14.1%, and 6.4%, respectively. There were no survival differences noted according to sex or race. Patients aged<60 years were found to have a better median OS compared with patients aged>or=60 years (median OS, 7 months vs 3 months; P=.007), although the 5-year OS was equally poor in both groups (6.3% vs 6.4%, respectively). During the same period, 49,106 patients with MM were identified. Unlike MM, in which there has been a modest but statistically significant improvement in OS and DSS noted over time, no significant improvement was evident for PCL. The poor long-term outcome and the lack of survival improvement in PCL suggest the need for better therapeutic options for these patients.

Interferon and ribavirin vs interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon: A meta-analysis of randomized trials.

Hepatitis C is the leading cause of chronic liver disease in the United States. Several trials have found that interferon and ribavirin combination therapy is more efficacious than interferon monotherapy for previously untreated patients and those who relapsed after prior interferon monotherapy, but its effectiveness for nonresponders to prior interferon monotherapy is unclear. To assess the efficacy and safety of interferon and ribavirin vs interferon alone for treatment of patients with chronic hepatitis C who previously did not respond to interferon monotherapy. A systematic search was performed using MEDLINE and the Science Citation Index for publications from 1966 to December 1999. A manual reference search and a manual review of relevant specialty journals also were performed, and input from clinical hepatology experts was sought. Included studies were randomized, controlled clinical trials comparing interferon and ribavirin with interferon alone and reporting virological and biochemical outcomes after a follow-up period. Of 50 identified studies, 12 trials (941 patients) were included in the analysis. Two investigators reviewed trials independently for methods, inclusion and exclusion criteria, and outcomes. Disagreements were resolved by discussion. Abstracted data included study and patient characteristics and virological, biochemical, and histological outcomes. A quality evaluation questionnaire was used to score studies. The pooled virological response rate for combination therapy was 14% (95% confidence interval [CI], 11%-17%), with a risk difference favoring combination therapy of 7% (95% CI, 2%-13%). Use of interferon alfa-2a/2b and ribavirin, 1000 to 1200 mg/d, was associated with a pooled virological response rate of 18% and a risk difference of 16% (95% CI, 11%-21%). When interferon alfa-n/n3 and a lower dosage of ribavirin (600-800 mg/d) were used, the risk difference was 0% (95% CI, -7% to 7%). Combination therapy was associated with more adverse effects and an increased rate of discontinuation of treatment compared with interferon monotherapy. For chronic hepatitis C that is nonresponsive to prior interferon monotherapy, combination therapy is more effective than re-treatment with interferon alone. Response rates remain less than 20% even in the most responsive subgroups, demonstrating a need for better therapeutic options.