Phase I study of the combination of losoxantrone and cyclophosphamide in patients with refractory solid tumours

Losoxantrone is a DNA intercalator that was developed with the potential to replace anthracyclines. The recommended single agent dose of losoxantrone is 50 mg m−2 every 3 weeks. We conducted a phase I study of losoxantrone and a fixed dose of cyclophosphamide on a q3 weekly schedule. Forty-nine patients were enrolled, of which 46 were evaluable for toxicity. The dose-limiting toxicity was neutropenia at the maximum tolerable losoxantrone dose of 45 mg m−2. With granulocyte colony-stimulating factor support, significant further dose escalation of losoxantrone was achieved. Cardiotoxicity was seen with cumulative dosing. Pharmacokinetics of losoxantrone revealed linear kinetics and triphasic clearance, with significant interpatient variability. No objective responses were seen in this study. Neutropenia was dose-limiting in this combination with or without granulocyte colony-stimulating factor support. The recommended dose for further testing is cyclophosphamide 500 mg m−2 followed by losoxantrone 95 mg m−2 with granulocyte colony-stimulating factor support

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

Circadian regulation of hormone signaling and plant physiology

The survival and reproduction of plants depend on their ability to cope with a wide range of daily and seasonal environmental fluctuations during their life cycle. Phytohormones are plant growth regulators that are involved in almost every aspect of growth and development as well as plant adaptation to myriad abiotic and biotic conditions. The circadian clock, an endogenous and cell-autonomous biological timekeeper that produces rhythmic outputs with close to 24-h rhythms, provides an adaptive advantage by synchronizing plant physiological and metabolic processes to the external environment. The circadian clock regulates phytohormone biosynthesis and signaling pathways to generate daily rhythms in hormone activity that fine-tune a range of plant processes, enhancing adaptation to local conditions. This review explores our current understanding of the interplay between the circadian clock and hormone signaling pathways

Chiral vicinal diols as platforms for separable diastereomers in Johnson-Claisen rearrangement: a new short route to (-)-nor-canadensolide, (-)-canadensolide and (-)-sporothriolide

The chiral vicinal diols prepared by asymmetric dihydroxylation in high enantioselectivities provide an excellent platform for separable diastereomers in the Johnson-Claisen rearrangement. The separated syn-diastereomers were converted into the advanced gamma-(lactone-lactol) intermediates (in six steps, 26-27% overall yields) for the synthesis of (-)-nor-canadensoiide, (-)-canadensolide and (-)-sporothriolide. (C) 200

Arundic Acid a Potential Neuroprotective Agent: Biological Development and Syntheses

Arundic acid has been experimented in vitro and in vivo as a potential neuroprotective agent. It modulates astrocyte activation by inhibiting the enhanced astrocytic synthesis of S-100 beta protein, responsible for inducing neuronal death. The phase II clinical trials for the treatment of acute ischemic stroke, as well as clinical development in other neurodegenerative diseases including amytrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease are recently completed. There is no review published in this area since its discovery as potential neuroprotective agent and the various syntheses reported for this important non-natural compound. This review summarizes the studies towards the development of arundic acid as a neuroprotective agent, the biological studies in vitro and in vivo, the phase II trials and the various efforts made for its synthesis in the last two decades

A Concise Stereoselective Synthesis of the Tetracyclic Naphthoquinone (-)-Isagarin

A concise stereoselective synthesis of the tetracyclic naphthoquinone natural product (-)-isagarin has been completed in seven steps from known alkyne 5 (obtained from D-mannitol) by using Dotz benzannulation and intramolecular stereospecific dioxabicyclic ketal formation as key steps

Synthetic studies on C14 cembranoids: synthesis of C4-12 fragment of sarcophytonolides E-G and L and C5-11 fragment of sarcophytonolide L

An efficient stereoselective synthesis of C4-12 fragment of the cembranoids, sarcophytonolides E-G and L and C5-11 fragment of sarcophytonolide L is described. The C4-12 building block is efficiently assembled starting from chiral pool material (R)-carvone employing the Baeyer-Villiger oxidation, modified Knoevenagel condensation and asymmetric dihydroxylation as the key steps. The synthesis of C5-11 fragment is based on orthoester Johnson-Claisen rearrangement as the key step. (C) 2010 Elsevier Ltd. All rights reserved

A short enantioselective synthesis of (+)-eleutherin, (+)-allo-eleutherin and a formal synthesis of (+)-nocardione B

A short enantioselective synthesis of (+)-eleutherin, (+)-allo-eleutherin and the formal synthesis of (+)-nocardione B is described. The synthesis is completed in six steps in overall yields of 8% for eleutherin and 14% for allo-eleutherin. The synthetic strategy features ail efficient combination of the Dotz annulation reaction with a chiral alkyne and an oxa-Pictet Spengler reaction as the keys steps in the stereodivergent synthesis of (+)-eleutherin and (+)-allo-eleutherin. The synthesis of (S)-(+)-2-(2'-hydroxypropyl)-5-methoxy-1,4-naphthoquinone entails the formal synthesis of (+)-nocardione B. (c) 200

Stereoselective synthesis of (-)-1-epi-ventiloquinone L and (+)-ventiloquinone L, the monomeric unit of cardinalin 3

A stereoselective synthesis of (-)-1-epi-ventiloquinone L and (+)-ventiloquinone L, the monomeric unit of cardinalin 3 has been described. The synthesis is completed in 7 steps with 10.5% and 13% overall yields for (-)-1-epi-ventiloquinone L and (+)-ventiloquinone L respectively. The key steps involve Dotz benzannulation of carbene 5 with alkyne 6 to give a substituted naphthalene moiety and oxa-Pictet-Spengler reaction to install the 1,3-dimethylpyran moiety