The genetic response of zebrafish to each toxin can be read like a barcode, offering researchers a potential method for identifying the effects of the toxin on developing vertebrate embryos.

Zebrafish embryos were exposed to eleven common pollutants, including cadmium, mercury and arsenic, by a team led by Uwe Str?¤hle at the Institute of Toxicology and Genetics, Karlsruhe, Germany. The team monitored changes in gene-expression profiles in order to predict the chemical that the embryo had been exposed to; the results were clear-cut for 10 out of 11 toxins.

Zebrafish have previously found a role in toxicology tests, for example in testing sewage for the presence of toxins. However, these previous tests involved looking at adult fish or embryos. The new method developed by Str?¤hle and colleagues does distinguish individual genetic barcodes of chemicals and will help cope with the high demand from regulators and industry for reliable methods needed to evaluate the developmental toxicity of pharmaceuticals, industrial chemicals and waste products. The research may prove valuable for initiatives such as the European Union Registration, Evaluation and Authorisation of Chemicals programme (REACH) which was set up to improve the protection of human health and the environment through the better and earlier identification of the intrinsic properties of chemical substances.

"Zebrafish embryos offer a cheap and ethically acceptable vertebrate model that will not only be useful in the toxicological assessment of the tens of thousands of compounds to be tested under the REACH programme but can also help to evaluate the developmental toxicity of novel compounds at an early stage of drug development," says Str?¤hle.

This new work provides the basis for the development of large-scale systematic methods for identifying the potential of chemicals.

biomedcentral/

According to Gong, mutated EGFRs produce growth signals that drive uncontrolled lung tumor cell division. Inhibition of mutated EGFR is a very effective treatment for these types of lung cancers, she says.

Gong and her colleagues at Memorial Sloan-Kettering demonstrated how lung cancer cell lines with EGFR mutations undergo apoptosis when exposed to erlotinib. In particular, they found that such cells die by a mechanism called the intrinsic apoptotic pathway. Erlotinib, the researchers say, induces dramatic changes in the pro-apoptotic protein, BIM, and this protein is required for erlotinib-triggered cell death.

The improved understanding of how EGFR mutant cells actually respond to EGFR TKIs will help us to identify strategies to enhance tumor cell death and will also help us to look for possible reasons why tumor cells persist despite treatment, Gong said.

In studies of EGFR TKI-sensitive cancer cells, the researchers found that ABT-737 significantly enhanced erlotinib-induced cell death. It is proof of principle that you can enhance tumor response to EGFR TKIs by priming tumor cells to a more death “prone state with small molecules that manipulate the intrinsic apoptotic pathway, Gong said. We hope to design clinical trials based on this strategy, in order to achieve better and longer clinical responses for patients who benefit from EGFR TKIs.

Gong is part of the laboratory of William Pao, M.D., Ph.D. Their studies were funded by the Doris Duke Charitable Foundation and the Labrecque Foundation. ABT-737 is under development by Abbott Laboratories, Inc.

TRAIL-receptor antibodies synergize with chemotherapy to enhance anti-tumor activity in cholangiocarcinoma: Abstract B 50.

A common chemotherapy regimen, when given before either one of two engineered human antibodies, greatly increases the effectiveness of the antibodies against cholangiocarcinoma (CCA), a rare and deadly cancer of the ducts that drain bile from the liver, say researchers from Human Genome Sciences, Inc., a biopharmaceutical research company based in Rockville, Maryland. If their findings in cell culture and animal models of CCA can be applied to humans, the combination of cisplatin, 5-fluorouracil or gemcitabine with a TRAIL-receptor antibody would be the first effective treatment for this disease, they say.

The two antibodies react with different, yet related, cell surface proteins called TRAIL-R1 and TRAIL-R2, which are common to many human cancers. While they are distinct receptors, these two receptors both receive signals that activate biochemical pathways leading to programmed cell death, the researchers say. The TRAIL-R1 antibody (known as mapatumumab) and TRAIL-R2 antibody (lexatumumab) are both being evaluated in clinical trials by Human Genome Sciences.

Many cancers use the TRAIL pathway as a preferred way to die “ a dominant biochemical pathway “ and we are in the process of exploring how we can better activate the TRAIL pathways to enhance cell death in the tumor cell, said Robin C. Humphreys, Ph.D., associate director in the Oncology Research Department at Human Genome Sciences. When we pre-treat CCA cell lines with conventional chemotherapies, the drugs seem to increase the cytotoxicity of the TRAIL-receptor antibodies, as if conventional chemotherapy can lower the cell death threshold of cancer cells enough for the TRAIL pathway to be more effective.

Humphreys and his colleagues experimented with combinations of cisplatin, 5-fluorouracil and gemcitabine given with or prior to treatment with the human TRAIL-receptor antibodies in cholangiocarcinoma cell cultures. Their findings indicated that treating CCA cell lines with a single chemotherapeutic agent 24 hours before administering either antibody increased cytotoxicity, killing nearly 90 percent of cells. According to Humphreys, mouse xenograft studies showed that co- or pre-treatment of a CCA xenograft tumor with cisplatin or gemcitabine before administering mapatumumab significantly inhibited tumor growth and displayed tumor regression over the 40-day period of the trials.

Since human biliary cancer remains a relatively rare cancer, with an annual incidence of about one or two cases per 100,000 people in the Western world, there has been little research toward a specific treatment for this disease, the researchers contend. This pre-clinical data supports potential clinical trials of a TRAIL-R mAb and chemotherapy combination in CCA, Humphreys says.

aacr/