Treatment triggers targeted tumour infarcts in mice

THE LANCET

SCIENCE AND MEDICINE

Treatment triggers targeted tumour infarcts in mice t may be possible to make large tumours infarct by triggering thrombosis in tumour-associated blood vessels, according to researchers in the USA (Science 1997; 275: 547-50). Philip Thorpe of the University of Texas Southwestern Medical Center (Dallas, Texas) and colleagues bound an altered form of human tissue factor (TF) to an antibody against antigens on the endothelium of blood vessels in a tumour. Normally, TF plays a crucial role in the extrinsic coagulation pathway. But in their experiments Thorpe and his colleagues used a truncated form, tTF, that lacked the cell-surface domain of the normal protein. As TF

must be associated with a cell membrane for full activity, this alteration blocks its ability to trigger coagulation. Thorpe and colleagues hypothesised that they might be able to target specific vessels for thrombosis by joining tTF to an antibody that would bind selectively to the endothelium within tumours. This antibody, they hoped, would bring tTF close enough to the endothelial cell membrane to restore its activity and trigger the coagulation cascade. TIn order to test their theory, the researchers used a mouse model for neuroblastoma in which the endothelium of tumour vessels expresses the antigen I-Ad. The researchers found that when 21 of these mice were

Antisense drugs move towards the clinic

Indentifying fear requires an amygdala

n less than ten years, therapeutic antisense oligonucleotides have gone from a good idea on paper to a practical possibility. Antisense therapeutics represent a new type of pharmacology, Stanley Crooke of Isis Pharmaceuticals, Carlsbad, USA, explained at a Ciba Foundation meeting in London, UK, on Jan 10. “This is the first time that a drug has been designed to destroy its target”. Antisense drugs inhibit the flow of information from DNA to protein by interacting with RNA, “and most antisense oligonucleotides help destroy their RNA targets by providing recognition sites for RNase H, an enzyme that cuts double-stranded RNA”. In clinical trials, one antisense drug, ISIS 2302, prevented intracellular adhesion molecule-1 (ICAM-1) expression, said Crooke. ICAM-1 acts at early stages of inflammation and ISIS 2302 is being used in five phase-II trials in patients with Crohn’s disease, ulcerative colitis, psoriasis, rheumatoid arthritis, and after transplantation. The Crohn’s disease trial has just been completed. 15 patients with aggressive steroiddependent disease were treated with ISIS 2302 (at one of three doses) every other day for 1 month; five patients were given placebo. The drug was well tolerated at all doses, and at 6-months follow-up there was a substantial reduction of inflammation in patients given ISIS 2302.

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Jane Bradbury

Vol 349 • January 25, 1997

injected with a tTF-antibody construct, in which one arm of the antibody was specific for tTF and the other for the endothelial I-Ad antigen, eight (38%) had complete tumour regression and five (24%) had reductions in tumour volumes in excess of 50%. A histological study of mice receiving tTF-antibody treatments found that vessels throughout the tumours thrombosed within 30 min of injection, and within 24 h the tumours showed advanced necrosis. Normal tissue, on the other hand, seemed to have been spared. Thorpe said that clinical trials should begin within 2 years. Michael McCarthy

intonations was also poor. In a test of erbal and non-verbal expressions non-verbal sounds conveying basic of fear and anger are interpreted emotions (eg, growling), she had by the amygdala, report UK “highly impaired recognition of anger researchers Andrew Young of and fear, and normal performance for Cambridge’s Medical Research the other emotions”. Other studies of Council applied psychology unit and this woman also colleagues in Nature showed impaired (1997; 385: 254recognition of facial 57). They assessed expressions of fear the ability to recogand anger, says nise and interpret Young. These findemotional sounds ings are “consistent and voice inflections with impairment of a in a woman with mechanism geared bilateral damage to to interpreting emothe amygdala after tional signals regardepilepsy surgery. less of their source”. Despite normal Appreciation requires an amygdala Future work comprehension of includes further investigation of the meaning of “emotion” words, the impaired recognition of disgust in woman could not properly interpret people with Huntington’s disease vocal expressions of emotion. When (Brain 1996; 119: 1647–65). listening to sentences with neutral “Different emotions can be differencontent in varying tones of voice, she tially affected by different types of identified emotions significantly less brain injury”, says Young. well than controls. Recognition of emotion when neutral words (eg, carpet) were spoken with various Marilynn Larkin

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Ronald Grant Archives

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Oral HIV test found to be highly accurate multisite trial has shown that an oral test for HIV-1 is accurate and may be a safe alternative to serum testing. OraSure (Epitope, Oregon), consists of a treated cotton pad that is placed between the cheek and lower gum to draw in an IgGrich transudate. This can be tested by ELISA for anti-HIV-1 antibody and, if indicated, a western blot.

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Samples were collected from 3570 people. 2382 were thought to be at low risk for HIV-1 infection and 698 at high risk, 242 had AIDS, and 248 had conditions that are associated with an increase in false-positive results, such as autoimmune disease. Oral testing provided the correct result or would trigger appropriate tests in more than 99·9% of cases. 䡺

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