BH3 mimetics are a new class of proapoptotic anticancer agents that have shown considerable promise in preclinical animal models and early-stage human trials. These agents act by inhibiting the prosurvival function of one or more Bcl-2-related proteins. Agents that inhibit Bcl-x L induce rapid platelet death that leads to thrombocytopenia; however, their impact on the function of residual circulating platelets remains unclear. In this study, we demonstrate that the BH3 mimetics, ABT-737 or ABT-263, induce a time-and dose-dependent decrease in platelet adhesive function that correlates with ectodomain shedding of the major platelet adhesion receptors, glycoprotein Ib␣ and glycoprotein VI, and functional downregulation of integrin ␣ IIb  3 . Analysis of platelets from mice treated with higher doses of BH3 mimetics revealed the presence of a subpopulation of circulating platelets undergoing cell death that have impaired activation responses to soluble agonists. Functional analysis of platelets by intravital microscopy revealed a timedependent defect in platelet aggregation at sites of vascular injury that correlated with an increase in tail bleeding time.Overall, these studies demonstrate that Bcl-x L -inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets. (Blood. 2011;118(6):1663-1674) IntroductionApoptosis is an evolutionarily conserved process important for mammalian development, tissue homeostasis, and immune tolerance. Apoptosis also acts as an important barrier against malignant transformation. Resistance to apoptosis is a hallmark feature of cancer, and several pathways regulating apoptosis are commonly altered in human malignancies. 1,2 For example, Ͼ 50% of all human cancers contain mutations in the p53 tumor suppressor gene, with nearly all of these mutations preventing p53 from triggering apoptosis. 3 Furthermore, the overexpression or enhanced function of certain prosurvival proteins, such as Bcl-2, 2 Bcl-x L , 2 PI3K/Akt/mTOR, 4 and nuclear factor-B, 5 is found in many types of human cancers. As a consequence, strategies targeting specific prosurvival pathways have gained prominence as novel anticancer therapies.Progress unraveling the complex pathways underlying apoptosis and cell survival, and elucidation of their roles in human cancers, has led to the development of several potential anticancer drugs, such as inhibitors of the Bcl-2 protein family, 6 inhibitors of apoptosis (IAPs), 7 MDM2, 8 PI3K/Akt/mTOR, 9 as well as TNFrelated apoptosis-inducing ligand. 10 A particularly promising approach is the ability to inhibit tumor cell survival through the use of agents that mimic the proapoptotic Bcl-2 homology 3 (BH3) domain proteins. BH3 proteins play an important role in inducing apoptosis by antagonizing the function of prosurvival Bcl-2 family proteins. Preclinical studies with the BH3 mimetic ABT-737, which selectively antagonizes Bcl-2, Bcl-x L , and Bcl-w, have demonstrated potent cytotoxic activity a...
Rationale : Platelets are increasingly recognized as mediators of tumor growth and metastasis. Hypothesizing that activated platelets in the tumor microenvironment provide a targeting epitope for tumor-directed chemotherapy, we developed an antibody-drug conjugate (ADC), comprised of a single-chain antibody (scFv) against the platelet integrin GPIIb/IIIa (scFv GPIIb/IIIa ) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE). Methods : We developed an ADC comprised of three components: 1) A scFv which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets. 2) A highly potent microtubule inhibitor, monomethyl auristatin E. 3) A drug activation/release mechanism using a linker cleavable by cathepsin B, which we demonstrate to be abundant in the tumor microenvironment. The scFv GPIIb/IIIa -MMAE was first conjugated with Cyanine7 for in vivo imaging. The therapeutic efficacy of the scFv GPIIb/IIIa -MMAE was then tested in a mouse metastasis model of triple negative breast cancer. Results : In vitro studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity. In vivo fluorescence imaging demonstrated that the newly generated ADC localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established. Importantly, we demonstrated that the scFv GPIIb/IIIa -MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects. Conclusion : Here, we demonstrate the utility of a novel ADC that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor. This unique targeting mechanism, specific to the tumor microenvironment, holds promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack specific molecular epitopes for drug targeting.
Preoperative anaemia affects 13.9% of patients undergoing elective major surgery. The most common causes are iron deficiency and chronic diseases. The cause was unexplained in 25.5% of patients with anaemia. The prevalence of anaemia in different surgical specialties may have implications on the approach to screening, particularly in resource-limited areas.
Busulfan (Bu) is an alkylating agent widely used in conditioning regimes prior to stem cell transplantation (SCT), most commonly in combination with cyclophosphamide (Bu-cy) or fludarabine (Bu-flu) as myeloablative conditioning prior to allograft or with high-dose melphalan (Bu-mel) prior to autologous SCT. Despite many decades of Bu use, initially orally but now intravenously (IV), a paucity of pharmacokinetic (PK) and pharmacodynamic (PD) data exists to inform evidence-based guidelines as how best to balance the efficacy and toxicity of this agent. This is a non-randomized retrospective real-world study at three hospitals investigating the role of PK guidance in dosing Bu in the setting of IV Bu-mel autologous SCT. The primary intent was to examine how effectively PK assessment could be used to achieve a desirable drug exposure and to evaluate factors, particularly, age, sex, actual weight, body mass index (BMI), body surface area (BSA), disease, number of prior treatments, renal function, and the use of concomitant medications that may influence Bu exposure. All patients underwent PK analysis on a test dose of Bu (1.6 mg/kg, i.e., 50% of the first dose) on D-7 and subsequently received a second 1.6 mg/kg dose on D-6. Bu dose was calculated using actual body weight (ABW) if patients were less than ideal body weight (IBW), or adjusted ideal body weight (AIBW) if ABW was greater than IBW. Thereafter, at the discretion of the investigator, the group was divided into two; a weight-based cohort at two hospitals and a PK-guided cohort at the third hospital. Thirty-seven patients received PK-adjusted dosing guided by the results of the initial PK results, targeting a specific Bu exposure expressed as the area-under-the-concentration-versus-time curve (AUC) of between 4000 and 5000 μmol min/day (median 4800). The remaining 27 patients received unadjusted weight-based doses with a further three doses of 3.2 mg/kg of Bu infused over 180 min (D-5 to - 3) irrespective of their initial PK results. For the purposes of the analysis, we selected a target AUC of 4800 μmol min/day in this group, equivalent to the median targeted AUC in the PK-adjusted group. All patients subsequently had repeated PK analysis on D-5 after receiving their "therapeutic" Bu dose. Mel (140 mg/m or 100 mg/m) IV was given on D-2. Sixty-four adult patients were enrolled. Patients who received PK-guided Bu dosing received a higher median Bu dose than the unadjusted weight-based cohort (3.5 mg/kg vs 3.2 mg/kg respectively, p = 0.007). Eighty-one percent (30/37) of patients in the PK-guided group achieved their target AUC (± 15%) compared with 56% (15/27) in the weight-based cohort (p = 0.027). The respective median AUCs of 5064 μmol min/day (range 3639-6157 μmol min/day) and 4854 μmol min/day (range 3251-6305 μmol min/day) were not significantly different (p = 0.16). Multivariate analysis identified ABW as the only independent variable that affected the relationship between Bu dosing and exposure (p = 0.02) with heavier patients achieving lower than antic...
Background The perioperative module of the Australian Patient Blood Management guidelines recommended preoperative iron therapy for surgical patients with, or at risk of, iron deficiency anaemia. After implementing a preoperative haemoglobin optimization programme in our institution, an audit was undertaken to evaluate the benefit of preoperative iron therapy in ‘real world’ clinical practice. Methods Elective major surgery patients assessed in surgical pre‐admission clinics from 1 July 2013 to 30 June 2014 were screened for iron deficiency and anaemia. Those who were iron deficient (ferritin <30 μg/l), regardless of haemoglobin level, received either daily oral iron supplementation until day of surgery or intravenous iron polymaltose 1 g preoperatively (intervention group). Control patients who were not iron deficient were matched to the intervention group using propensity scores based on age, sex and surgical unit. The primary end‐point was the proportion of patients requiring perioperative red cell transfusion in intervention and control groups. Results One hundred and fourteen patients (8·75%) had iron deficiency. Ninety‐three patients received preoperative iron therapy, 17 (18·3%) of whom required red cell transfusions postoperatively. Of the 332 control patients, 71 (21·4%) required red cell transfusion. After adjusting for preoperative haemoglobin and time from screening to surgery, the odds of red cell transfusion were significantly lower in the intervention group compared to controls (odds ratio: 0·512, 95% confidence interval: 0·268–0·977; P = 0·04). Conclusion Preoperative iron therapy was associated with reduced need for postoperative red blood cell transfusion in elective major surgery patients who were initially iron deficient.
Pulmonary arterial hypertension (PAH) is a devastating progressive disease characterised by pulmonary arterial vasoconstriction and vascular remodelling. Endothelial dysfunction has emerged as a contributing factor in the development of PAH. However, despite progress in the understanding of the pathophysiology of this disease, current therapies fail to impact upon long-term outcomes which remain poor in most patients. Recent observations have suggested the disturbances in the balance between ATP and adenosine may be integral to the vascular remodelling seen in PAH. CD39 is an enzyme important in regulating these nucleos(t)ides which may also provide a novel pathway to target for future therapies. This review summarises the role of adenosine signalling in the development and progression of PAH and highlights the therapeutic potential of CD39 for treatment of PAH.
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