The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice

5,6-dimethylxanthenone-4-acetic acid, a novel antivascular anticancer drug, has completed Phase I clinical trial. Its actions in mice include tumour necrosis factor induction, serotonin release, tumour blood flow inhibition, and the induction of tumour haemorrhagic necrosis and regression. We have used mice with a targeted disruption of the tumour necrosis factor receptor-1 gene as recipients for the colon 38 carcinoma to determine the role of tumour necrosis factor signalling in the action of 5,6-dimethylxanthenone-4-acetic acid. The pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid, as well as the degree of induced plasma and tissue tumour necrosis factor, were similar in tumour necrosis factor receptor-1−/− and wild-type mice. However, the maximum tolerated dose of 5,6-dimethylxanthenone-4-acetic acid was considerably higher in tumour necrosis factor receptor-1−/− mice (>100 mg kg−1) than in wild-type mice (27.5 mg kg−1). The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (25 mg kg−1) was strongly attenuated in tumour necrosis factor receptor-1−/− mice. However, the reduced toxicity in tumour necrosis factor receptor-1−/− mice allowed the demonstration that at a higher dose (50 mg kg−1), 5,6-dimethylxanthenone-4-acetic acid was curative and comparable in effect to that of a lower dose (25 mg kg−1) in wild-type mice. The 5,6-dimethylxanthenone-4-acetic acid -induced rise in plasma 5-hydroxyindoleacetic acid, used to reflect serotonin production in a vascular response, was larger in colon 38 tumour bearing than in non-tumour bearing tumour necrosis factor receptor-1−/− mice, but in each case the response was smaller than the corresponding response in wild-type mice. The results suggest an important role for tumour necrosis factor in mediating both the host toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid, but also suggest that tumour necrosis factor can be replaced by other vasoactive factors in its antitumour action, an observation of relevance to current clinical studies

An EFQM excellence model for higher education quality assessment

The long-term advancement in the higher education sector, where the universities have to conduct their activities in a more business-like fashion requires a permanent strive for excellence. On the other hand, there is still no consensus on how best to assess and manage quality within higher education institutions. The present article discusses the adaptation of a quality model based on the European Framework for Quality Management (EFQM) for systematic measurement of quality in higher education sector.Maziar Arjomandi, Colin Kestell and Paul Grimshawhttp://www.aaee.com.au

The anatomy of Engineering education: Parallels in teaching the practical aspects of Anatomy and Engineering

Traditional University disciplines, such as Anatomy and Engineering, have over the course of their history experienced a long and varied development. For example, in the Engineering discipline computer simulations, videos and virtual laboratories are increasingly replacing laboratory experiments as student numbers increase. Similarly, within the Anatomy, in more recent times with the increasing numbers of students, the use of cadaveric dissection laboratory classes to teach Anatomy has been enhanced or replaced with online learning and 3D models. The advent of modern multi-disciplinary University degrees in Engineering, including Orthopaedic, Biomedical and Sports Engineering, require effective pedagogy paradigms of both Anatomy and Engineering. This paper explores the parallels that exist in the current teaching trends within these two disciplines with the aim of evaluating whether common codes of effective practice exist and can be implemented. A review of both Anatomy and Engineering learning methods was undertaken and the parallels in good teaching practice summarized and compared. The findings show that effective teaching strategies consist of the use of modern technology and the retention of traditional methods in both disciplines. The knowledge gained will benefit the interrelated development by showing how common techniques can and do work. Furthermore, the findings may be applicable to education methods in other science based disciplines.Paul Grimshaw, Colin Kestell, Maziar Arjomandi, Pascual Marqués-Bruna, Shylie Mackintosh and Michel de Jonge.http://www.aaee.com.au

Transport of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid and its acyl glucuronide by human intestinal caco-2 cells

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent cytokine inducer, exhibited marked antitumor activity when given as multiple oral doses in mice. The aim of this study was to examine the transport of DMXAA and its acyl glucuronide (DMXAA-G) using the human Caco-2 cells. DMXAA was minimally metabolized by Caco-2 cells and both DMXAA and DMXAA-G were taken up to a minor extent by the cells. The permeability coefficient (Papp) values of DMXAA over 10-500 ?M were 4 × 10-5 cm/s to 4.3 × 10-5 cm/s for both apical (AP) to basolateral (BL) and BL-AP transport, while the Papp values for the BL to AP flux of DMXAA-G were significantly greater than those for the AP to BL flux, with R net values of 4.5-17.6 over 50-200 ?M. The BL to AP active efflux of DMXAA-G followed Michaelis-Menten kinetics, with a Km of 83.5 ± 5.5 ?M, and Vmax of 0.022 ± 0.001 nmol/min. The flux of DMXAA-G was energy and Na+-dependent and MK-571 significantly (P < 0.05) inhibited its BL to AP flux, with an estimated Ki of 130 ?M. These data indicate that the transport of DMXAA across Caco-2 monolayers was through a passive process, whereas the transport of DMXAA-G was mediated by MRP1/2

Measurement of plasma 5-hydroxyindoleacetic acid as a possible clinical surrogate marker for the action of antivascular agents.

BACKGROUND: Serotonin (5HT), a naturally occurring vasoactive substance, is released from platelets into plasma under various pathological conditions. Recently, anticancer drugs that act by selectively disrupting tumour blood flow have been found to increase plasma 5HT concentrations in mice. Two such antivascular agents, flavone acetic acid (FAA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), have completed Phase I clinical trial and raise the important question of whether suitable surrogate markers for antivascular effects can be identified. METHODS: 5HT is unstable to storage, precluding routine clinical assay, but the 5HT metabolite, 5-hydroxyindoleacetic acid (5HIAA) accumulates in plasma following 5HT release and is a more suitable marker because of its greater stability. We have developed an automated procedure for the assay of the low concentrations of 5HIAA found in humans by combining solid-phase extraction with high-performance liquid chromatography (HPLC). RESULTS: Efficient separation of 5HIAA from possible interfering substances in human plasma, including a variety of pharmaceutical agents, was achieved on C18 columns using cetyltrimethylammonium bromide (CETAB) as an organic modifier. Adequate precision, accuracy and sensitivity were achieved by electrochemical detection (ECD) at +400 mV. Analysis of plasma from two patients treated with DMXAA in a Phase I trial demonstrated DMXAA-induced elevation of plasma 5HIAA with a time course similar to that previously described in mice. CONCLUSIONS: Measurement of changes in plasma 5HIAA provides a new approach to the monitoring of therapies with an antivascular effect. The assay is sensitive to dietary sources of 5HT, which should be minimised

Transport of thalidomide by the human intestinal Caco-2 monolayers

Studies in patients have indicated that the oral absorption of thalidomide is considerably variable at high doses (>200 mg/day). The aim of this study was to investigate the transport of racemic thalidomide using human colon cancer cell line (Caco-2) monolayers, which have been widely used to investigate drug permeability. A typical 21-day protocol was used to prepare Caco-2 monolayers. Thalidomide was determined by a validated high performance liquid chromatography method with ultraviolet detection. The integrity of Caco-2 monolayer was confirmed when the transepithelial electrical resistance (TEER) exceeded 300 Omega center dot cm(2), and the leakage of C-14-manitol was <1% per hour. Uptake of thalidomide by Caco-2 cells was very limited (up to 2.1%). The transport of thalidomide appeared to be linear up to 1 hr. Our study indicated that the permeability coefficients (P-app) of thalidomide at 2.5-300 mu M from the apical (AP) to basolateral (BL) and from BL to AP side was 2-6 x 10(-5) cm/sec, with a marked decrease in P-app values from AP to BL at increased thalidomide concentration. The transport of thalidomide was sodium-, temperature- and pH-dependent, as replacement of extracellular sodium chloride or reducing temperature and apical pH can result in significant decreases in the Papp values. Additional data indicated that transport of thalidomide is energy-dependent, as it was significantly (P < 0.05) inhibited by the ATP inhibitors, sodium azide and 2,4-dinitrophenol. In addition, DL-glutamic acid, cytidine, diprodomole, papaverine, quinidine, and cyclophosphamide significantly (P < 0.05) inhibited the transport of thalidomide, while the P-glycoprotein inhibitor verapamil and other nucleosides and nucleotides such as thymidine and guanine had no effect. These results indicated that thalidomide was rapidly transported by Caco-2 monolayers, and this might involve a saturable energy-dependent transporter