Induction of tumour necrosis factor-α by single and repeated doses of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a low-molecular-weight biological response modifier scheduled for clinical evaluation, induced synthesis of tumour necrosis factor- (TNF-) in serum of mice, with maximal activity being observed at 2–3 h after administration. At a dose of 27.5 mg/kg, DMXAA induced similar TNF- concentrations as did flavone-8-acetic acid given at its maximum tolerated dose (MTD; 330 mg/kg), whereas 8-methylxanthenone-4-acetic acid, which has no antitumour activity, did not induce serum TNF- at its MTD (440 mg/kg). The dependence of schedule on TNF- induction was studied by giving DMXAA to mice in two doses of 27.5 mg/kg each separated by different intervals. An interval of 0 (i.e 55 mg/kg given in a single dose) produced a TNF- concentration 9-fold that produced hy a single dose of 27.5 mg/kg. This dose, although higher than the MTD of 30 mg/kg, did not affect the health of mice at the time of assay (3 h). An interval of 1 day produced very low levels of serum TNF- after the second injection. An interval of 3 days produced high levels of serum TNF- after the second injection (9-fold that detected in mice receiving 27.5 mg/kg in a single dose) but no long-term toxicity, whereas an interval of 7 days produced an intermediate response. Thus, the first dose can either potentiate or suppress the TNF- response to a second dose. Mice with advanced subcutaneous colon 38 tumours were treated either with a single dose of DMXAA (27.5 mg/kg) or with a divided dose (two doses of 27.5 mg/kg given 3 days apart). Both the cure rate and the tumour-growth delay were enhanced by the divided-dose schedule. The results are relevant to the design of clinical administration schedules of DMXAA and emphasise the importance of TNF- induction in the antitumour response.This study was supported by the Auckland Division of the Cancer Society of New Zealand and by the Health Research Council of New Zealand     

Haematological effects in mice of the antitumour agents xanthenone-4-acetic acid, 5,6-methyl-xanthenone-4-acetic acid and flavone acetic acid

Summary Treatment of C₅₇Bl/6×DBA/2 mice with the maximal tolerated dose of flavone-8-acetic acid (FAA, 1300 mol/kg), xanthenone-4-acetic acid (XAA, 1090 mol/kg), or its dose-potent derivative 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA, 100 mol/kg) resulted within 24 h in a dramatic reduction in the number of circulating lymphocytes, an elevation in haemoglobin concentrations and a reduction in platelet numbers. Neutrophil counts either remained unchanged or were slightly elevated. All three compounds caused a marked loss of cells in the thymus. Examination of histological sections of thymus at 48 h following treatment with XAA revealed a selective depletion of cortical thymocytes and no effects on the epithelium or other thymic structures. A transient decrease in cell numbers was seen in the spleen and femoral bone marrow, with recovery to normal levels occurring within 3 days. The number of haemopoietic stem cells, colony-forming units in culture (CFU-c), in the femoral bone marrow increased after drug administration despite the occurrence of a decrease in the overal number of cells in the femur. In contrast to the increase in CFU-c numbers seen in vivo, 2 h exposure of bone-marrow cells to FAA, XAA or 5,6-MeXAA in vitro resulted in a decrease in the surviving fraction of CFU-c. The results are consistent with the hypothesis that the in vivo haematological effects of these compounds are indirect, perhaps being mediated through the induction of cytokines, and contrast with the haematological effects of conventional antitumour agents. The biochemical and haematological effects are unlikely to be the cause of the acute toxicity observed for these compounds.This research was supported by the Auckland Division of the Cancer Society of New Zealand, the Medical Research Council of New Zealand, The Todd Foundation and a Warner-Lambert Laboratory Fellowship     

CT and DSA appearances of a ruptured congenital arteriovenous malformation of the posterior mediastinal aorta

A case of symptomatic congenital arteriovenous malformation detected in an adult patient is presented. The diagnosis was not suspected clinically but was demonstrated by CT and digital subtraction angiography. Although very rare, a congenital arteriovenous malformation of the posterior mediastinal aorta could present as a catastrophic event if it ruptures. Serpiginous vascular channels in the retro-oesophageal posterior mediastinum on CT and angiography should raise the possibility of an arteriovenous malformation.     

Canal geometry changes associated with axial compressive cervical spine fracture

STUDY DESIGN: A laboratory study using isolated ligamentous human cadaveric cervical spines to investigate canal occlusion during (transient) and after (steady-state) axial compressive fracture. OBJECTIVES: To determine whether differences exist between transient and postinjury canal occlusion under axial compressive loading, and to examine the effect of loading rate on canal occlusion. SUMMARY OF BACKGROUND DATA: Prior studies have shown no correlation between neurologic deficit and canal occlusion measurements made on radiographs and computed tomography scans. The authors hypothesized that postinjury radiographic assessment does not provide an appreciation for the transient occlusion that occurs during the traumatic fracture event, which may significantly affect the neurologic outcome. METHODS: Twelve human cervical spines were instrumented with a specially designed canal occlusion transducer, which dynamically monitored canal occlusion during axial compressive impact. Six specimens were subjected to a fast-loading rate (time to peak load, approximately 20 msec), and the other six were subjected to a slow-loading rate (time to peak load, approximately 250 msec). After impact, two different postinjury canal occlusion measurements were performed. RESULTS: Each of the six specimens subjected to the fast-loading rate incurred burst fractures, whereas the slow-loading rate produced six wedge-compression fractures. For the fast-rate group, the postinjury occlusion-measurements were significantly smaller than the transient occlusion. In contrast, transient occlusion was not found to be significantly different from postinjury occlusion in the slow-rate group. All of the comparisons between loading rate groups showed significant differences, with the fast-rate fractures producing larger amounts of canal occlusion in every category. CONCLUSIONS: The findings indicate that even if canal occlusion could be measured immediately after axial compressive trauma, the measurement would underestimate the maximal amount of transient canal occlusion. Therefore, postinjury measurement of canal occlusion may indicate a smaller degree of neurologic deficit than what might be expected if the transient occlusion could be measured.     

Thalidomide metabolites in mice and patients with multiple myeloma.

PURPOSE:This research examines the profile of metabolites of thalidomide that are formed in refractory multiple myeloma patients undergoing thalidomide therapy in comparison with those that are detected in healthy mice. EXPERIMENTAL DESIGN: Urine or plasma samples from patients during thalidomide therapy (100-400 mg daily), or from mice treated i.p. (100 mg/kg) or p.o. with thalidomide (50 mg/kg) were analyzed using liquid chromatography-mass spectrometry. Metabolites in each of the peaks observed in the UV- and mass spectrometry-detected high-performance liquid chromatography traces were identified by comparison of retention times and spectra with those of authentic standards. RESULTS: Plasma and urine samples from mice 4 h after treatment with thalidomide contained eight major metabolites formed by hydroxylation and/or hydrolysis of thalidomide. In contrast, urine samples from seven multiple myeloma patients at steady state levels of thalidomide therapy showed the presence of only three hydrolysis breakdown products and no hydroxylated metabolites. CONCLUSIONS: Our results show that thalidomide metabolite profiles in multiple myeloma patients differ considerably from those in mice. The lack of measurable hydroxylated metabolites in urine and in 1 case plasma of these patients suggests that such metabolites are not responsible for the therapeutic effects of thalidomide in multiple myeloma. We suggest that thalidomide may act directly, down-regulating growth factors essential for multiple myeloma growth.     

Rates of, and the factors affecting, cycle helmet use among secondary schoolchildren in East Sussex and Kent

Objectives—To assess the level of cycle helmet wearing among young people in two counties in the South East of England in 1994, and to identify the factors associated with helmet wearing.