Citations

Abstract Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.

The neurotransmitter dopamine and its dopamine receptor D2 (D2DR) agonists are known to inhibit vascular permeability factor/vascular endothelial growth factor (VEGF)-mediated angiogenesis and vascular permeability. Lung injury is a clinical syndrome associated with increased microvascular permeability. However, the effects of dopamine on pulmonary edema, a phenomenon critical to the pathophysiology of both acute and chronic lung injuries, have yet to be established. Therefore, we sought to determine the potential therapeutic effects of dopamine in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Compared with sham-treated controls, pretreatment with dopamine (50 mg/kg body wt) ameliorated LPS-mediated edema formation and lowered myeloperoxidase activity, a measure of neutrophil infiltration. Moreover, dopamine significantly increased survival rates of LPS-treated mice, from 0–75%. Mechanistically, we found that dopamine acts through the VEGF-VEGFR2 axis to reduce pulmonary edema, as dopamine pretreatment in LPS-treated mice resulted in decreased serum VEGF, VEGFR2 phosphorylation, and endothelial nitric oxide synthase phosphorylation. We used D2DR knockout mice to confirm that dopamine acts through D2DR to block vascular permeability in our lung injury model. As expected, a D2DR agonist failed to reduce pulmonary edema in D2DR−/− mice. Taken together, our results suggest that dopamine acts through D2DR to inhibit pulmonary edema-associated vascular permeability, which is mediated through VEGF-VEGFR2 signaling and conveys protective effects in an ALI model.

Haloperidol is a butyrophenone neuroleptic agent characterized as a high-affinity dopamine antagonist, originally used for the treatment of schizophrenia. Awareness of the role dopamine plays in many symptoms in palliative care, such as nausea, vomiting, and delirium, has led to the use of dopamine antagonists such as haloperidol for the treatment of these symptoms in the palliative care setting. Listed as 1 of the 25 important drugs in palliative care, haloperidol can be administered by multiple routes and can be given without dose alteration in the setting of both renal and hepatic insufficiency. Haloperidol is extensively metabolized in the liver, with CYP3A4 the chief cytochrome oxidase responsible for metabolism. This article will review the pharmacology, pharmacokinetics, and current uses of haloperidol in palliative medicine. There will be an examination of the evidence base for the use of haloperidol in palliative medicine.

Transcription factors are proteins that regulate gene expression by modulating the synthesis of messenger RNA. Since this process is often one dominant control point in the production of many proteins, transcription factors represent the key regulators of numerous cellular functions, including proliferation, differentiation and apoptosis. Pancreatic cancer progression is characterised by activation of inflammatory signalling pathways converging on a limited set of transcription factors that fine-tune gene expression patterns contributing to the growth and maintenance of these tumours. Thus strategies targeting these transcriptional networks activated in pancreatic cancer cells could block the effects of upstream inflammatory responses participating in pancreatic tumorigenesis. The authors review this field of research and summarise current strategies for targeting oncogenic transcription factors and their activating signalling networks in the treatment of pancreatic cancer.