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Antibody could overcome the "resistance to the kiss of death" in cancer cells

Studies at MedUni Vienna – TRAIL signal path could be enhanced – Cooperation with Chinese scientists 

(Vienna/Beijing, 12 April 2010) In principle, cancer cells – including those of otherwise highly dangerous ovarian carcinomas – should respond with suicide (apoptosis) to a signal they receive at particular surface receptors (TRAIL receptors). But the drugs developed to date for this reason have shown relatively little effect. In ovarian cancer there is obviously resistance to it. A team of scientists around Michael Krainer, head of the working group for molecular genetics at the Department of Medicine I of MedUni Vienna, have now been able to identify a possible starting point to overcome this shortcoming.

The scientists have now published their findings online in the journal "Molecular Cancer Therapy" of the American Association for Cancer Research (AACR). Activities have been supported by the Austrian Science Fund FWF.

In principle, a "kiss of death" to TRAIL receptors by substances that bind to these docking sites is a good way to combat cancer cells. This mechanism, which is triggered by the messenger substance TRAIL (Tumour Necrosis Factor Related Apoptosis Inducing Ligand), also exists in ovarian cancer cells. But ovarian cancer tumours develop although this defence mechanism is in place and only respond insufficiently to such stimuli.

This is precisely the point which the work of the Vienna study group focuses on. Says Krainer: "Chinese researchers from Beijing have supplied us with a monoclonal antibody that was developed there. In the beginning we acquired it as a reagent. Although AD5-10 binds very specifically to those receptors that usually receive and transfer the TRAIL signal this is obviously at a slightly different place, so the place for the TRAIL signal (note: to commit "suicide") remains free."

If AD5-10 is now combined with substances that act as a "kiss of death" for the malignant cells, resistance against it will probably end. Says Krainer: "It truly works. We have been able to demonstrate in cell cultures and animal models that TRAIL resistant tumour cells of ovarian carcinomas again become susceptible to TRAIL if TRAIL and AD5-10 co-exist."

Krainer also assumes that AD5-10 could increase the effectiveness of frequently used chemotherapeutics. For this reason he examined the interactions of AD5-10 with a large number of drugs that are used to treat ovarian cancer. These studies also proved successful: "We were able to show in cell cultures that the combined impact of AD5-10 and carboplatin – a chemotherapeutic often used in treatment – was greater than the sum of effects when administered separately. In the animal model it was actually also found that AD5-10 can neutralise resistance against carboplatin."

The team headed by this scientist have also observed that this anti-tumoral effect of AD5-10 will only occur if so-called "natural killer cells" (or NK cells) are present in the micro-environment of the tumour. This is exciting evidence for Krainer that these cells fulfil a major function in the apoptosis that is initiated by AD5-10. The Vienna scientists are attempting to organise a clinical trial on patients with their Chinese partners.