Featured Research

from universities, journals, and other organizations

Novel Drug Screening Method: Informative Swellings

October 11, 2009
ETH Zurich
A screening method for bioactive small molecules to treat vascular diseases and an in vivo functional test in a whole animal at the same time: researchers achieved this feat with the aid of the frog Xenopus.

Blood vessel defects are visualized in Xenopus tadpoles. The bioactive compound with the abbreviation Cyclo-7 (top row) prevents the formation of new blood vessels (arrow). For comparison, pictures of the control animals are also shown (bottom row).

A screening method for bioactive small molecules to treat vascular diseases and an in vivo functional test in a whole animal at the same time: ETH Zurich researchers at the Institute of Pharmaceutical Sciences achieved this feat with the aid of the frog Xenopus.

Related Articles

How does one identify new bioactive compounds that can serve as a basis for the development of novel or more effective drugs? This question – which costs millions of dollars to answer – is a fundamental one for both academic scientists working in pharmaceutical sciences and the pharmaceutical industry. Accordingly, the search for new, low-cost, and effective drug screening methods is intense.

However, the search for novel drug candidates is anything but trivial. The predominant strategy used over the last decades consists, first of all, in clarifying the biochemical processes underlying a disease, then identifying an appropriate drug target, and finally developing an assay that allows the screening of chemical libraries for small molecules that interfere with the target. This approach is, however, very expensive and demands a great deal of background knowledge.

A great leap forward with a frog

It would be simpler, if one could use whole organisms to which small molecules would be administered and which would display an easily readable response in response to active substances affecting the development or function of a particular organ. The advantage of such an approach would be that the screening method would be directly linked to an experiment in a whole animal, a step that does not take place until much later in the standard approach of drug development.

Professor André Brändli’s group at the Institute of Pharmaceutical Sciences of ETH Zurich has made a giant leap towards such a simple test method by using tadpoles of the African clawed frog Xenopus laevis. André Brändli, who was appointed to a chair at the Ludwig-Maximilians-Universität Munich in July, successfully developed in this animal model a test method for compounds that influence angiogenesis (vascularisation). The corresponding study was published recently in the scientific journal Blood. Compounds that disrupt angiogenesis are very important, because, among other things, they can also be used against various types of cancer. This is because tumor growth is dependent on newly forming blood vessels.

A two-step drug screening method

What is the basis of this novel drug screening method? Brändli and his team used tadpoles of the African clawed frog Xenopus laevis, which are a few millimetres long. The tadpoles are just under 36-hours old at this time, and thus at the developmental stage, when they form new vessels. Because the tadpoles’ skin is permeable to small molecules, the researchers are able to add the test compounds directly to the liquid in which the tadpoles are kept. Afterwards, they examine the animals under a microscope, without any further treatment, for any detectable signs indicating changes in the vascular system.

In practice, they look in the first step of the method for evidence of edema, tissue swellings that occur when there are defects in the formation of vessels or kidneys. These are easily detectable because Xenopus tadpoles are transparent. If there are other peculiarities, e.g. the tadpoles either die or show specific pigmentation defects, the researchers also record these facts. For each active compound identified in the first step of the method, the scientists analyse its effects on angiogenesis more precisely in a second step in which they specifically mark the lymph and blood vessels with stains. As a result, they can determine the exact changes, be it the reduction or absence of a vessel, under the microscope.

A frog finds its way to the library

André Brändli had already carried the idea for this elegant screening method around with him for several years. As a developmental biologist who had already worked with Xenopus for years, he knew the advantages of his favorite animal model: a short generation time, easy to handle, and the availability of thousands of tadpoles at a reasonable price. Importantly, tadpoles develop into vertebrate animals with four limbs and many of the developmental mechanisms used along this process are similar to those required for mammalian development.

However, to prove that the tadpoles really are suitable for drug screening purposes, more was needed, namely large collections of chemical substances. Brändli had access to these from 2006 onwards when the Institute of Pharmaceutical Sciences purchased various chemical libraries.

The researcher made use of this convenient situation, and, together with his team, he tested 1280 substances that were known to be bioactive. The screen revealed that 32 of them affected the vascular system. A few of them act on both lymph and blood vessels, others on only one vessel system. In this respect, the fact that there are substances that influence the lymph system specifically is particularly interesting because there had hitherto been no convenient in vivo test system for this vessel type.

However, the quality of the screening method became apparent not only in the number of 32 bioactive substances identified and the ability to make distinctions with regard to either activities, but also by the fact that the method reliably detected all the active compounds already known to have vessel-system relevance. Next, Brändli teamed up with his institute colleague Professor Michael Detmar, a specialist on vascular development in mice, to demonstrate that the identified compounds were effective not only in tadpoles but also in mammals, Detmar and his team successfully proved for one compound (7-chloro-4-hydroxy-2-phenyl-1,8-naphthyridine), which inhibits blood and lymph angiogenesis in Xenopus, that it also counteracts artificially stimulated angiogenesis in the mouse. This demonstrated unequivocally that the Xenopus drug screening method is also pertinent for mammals.

Xenopus drug screening convinces the industry

Brändli is convinced that he has developed with Xenopus tadpoles a highly efficient, sensitive in vivo test method to discover novel small molecules that can affect angiogenesis. He says that his in vivo screening methodology, for which a patent application has been filed, also enables the discovery of substances that only become active in a whole organism and would therefore not be found with an in vitro test method using cell cultures. However, the researcher is not the only one who is convinced by the potential of drug screening in Xenopus tadpoles. Various pharmaceutical companies in Switzerland and abroad have also already expressed their interest in the new screening methodology.

Brändli now hopes that he will be able to build up a long-term partnership with the pharmaceutical industry. Drug candidates identified in the Xenopus drug screen are to be developed further in collaboration with the pharmaceutical industry to yield optimized variants that, ultimately, will be able to enter clinical trials. However, Brändli is under no illusions: even though the discovery of a drug candidate and the initial tests in an animal model represent important, decisive steps, the road ahead to an approved drug is still long and rocky.

Story Source:

The above story is based on materials provided by ETH Zurich. Note: Materials may be edited for content and length.

Journal References:

  1. Wheeler et al. Simple vertebrate models for chemical genetics and drug discovery screens: lessons from zebrafish and Xenopus. Developmental Dynamics, 2009; 238 (6): 1287 DOI: 10.1002/dvdy.21967
  2. Kalin et al. An in vivo chemical library screen in Xenopus tadpoles reveals novel pathways involved in angiogenesis and lymphangiogenesis. Blood, 2009; 114 (5): 1110 DOI: 10.1182/blood-2009-03-211771

Cite This Page:

ETH Zurich. "Novel Drug Screening Method: Informative Swellings." ScienceDaily. ScienceDaily, 11 October 2009. <www.sciencedaily.com/releases/2009/09/090912145157.htm>.
ETH Zurich. (2009, October 11). Novel Drug Screening Method: Informative Swellings. ScienceDaily. Retrieved April 19, 2015 from www.sciencedaily.com/releases/2009/09/090912145157.htm
ETH Zurich. "Novel Drug Screening Method: Informative Swellings." ScienceDaily. www.sciencedaily.com/releases/2009/09/090912145157.htm (accessed April 19, 2015).

Share This

More From ScienceDaily

More Health & Medicine News

Sunday, April 19, 2015

Featured Research

from universities, journals, and other organizations

Featured Videos

from AP, Reuters, AFP, and other news services

Our Love Of Puppy Dog Eyes Explained By Science

Our Love Of Puppy Dog Eyes Explained By Science

Newsy (Apr. 17, 2015) — Researchers found a spike in oxytocin occurs in both humans and dogs when they gaze into each other&apos;s eyes. Video provided by Newsy
Powered by NewsLook.com
Dr. Oz Under Fire For 'Quack Treatments' Yet Again

Dr. Oz Under Fire For 'Quack Treatments' Yet Again

Newsy (Apr. 17, 2015) — Ten doctors signed a letter urging Columbia University to drop Dr. Oz as vice chair of its department of surgery, saying he plugs "quack" treatments. Video provided by Newsy
Powered by NewsLook.com
Scientists Find Link Between Gestational Diabetes And Autism

Scientists Find Link Between Gestational Diabetes And Autism

Newsy (Apr. 17, 2015) — Researchers who analyzed data from over 300,000 kids and their mothers say they&apos;ve found a link between gestational diabetes and autism. Video provided by Newsy
Powered by NewsLook.com
Video Messages Help Reassure Dementia Patients

Video Messages Help Reassure Dementia Patients

AP (Apr. 17, 2015) — Family members are prerecording messages as part of a unique pilot program at the Hebrew Home in New York. The videos are trying to help victims of Alzheimer&apos;s disease and other forms of dementia break through the morning fog of forgetfulness. (April 17) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.


Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News


Free Subscriptions

Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile

Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?

Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins