Oct 18 2005
The humble yeast has revealed the molecular workings of an anti-cancer drug that stops the growth and spread of tumours in humans by starving their blood supply.
Until now, University of New South Wales scientists who developed the drug (GSAO) knew that it was lethal against endothelial cells but not why it had no direct impact on tumours themselves.
The new study reveals that endothelial cells lack the "transport protein" that tumours use to eject foreign molecules that invade their cell structure.
Endothelial cells are the building blocks of blood vessels. Cancer cells rely on blood vessel growth, known as angiogenesis, to grow and spread to other parts of the body.
"It's very sexy science," says one the research authors, Professor Philip Hogg, a biochemist with the UNSW Centre for Vascular Research and the Children's Cancer Institute Australia. "We now understand how an anti-cancer drug works in humans thanks to genetic studies using the humble yeast cell."
Published in today's edition of the prestigious Journal of the National Cancer Institute, the study reveals how researchers "genetically fingerprinted" the transport protein by using genetically modified (mutant) yeast cells. The researchers used 4800 yeast mutants that represent every non-essential gene in the genome.
"The mutant yeast cells that were vulnerable to the drug lacked the protein that enables them to eject the drug across their cell membrane," says Professor Ian Dawes, a study co-author from the UNSW Ramaciotti Centre for Gene Function Analysis.
"Yeast cells that lacked the protein died, while those that had the protein didn't," says Dawes. "That told us there was a specific gene encoding a protein that's vital for a cell to protect itself against GSAO."
Once the researchers knew this they looked for and found a corresponding protein in humans, known as a multi-drug resistance associated protein (MRP).
"The presence of these transport proteins in tumours is one of the reasons that anti-cancer drugs such as chemotherapy medicines fail against cancer," says Professor Hogg.
"The reason that GSAO is effective is that it targets tumours indirectly by attacking the endothelial cells that lack this transport protein. So GSAO is lethal against tumours because it chokes the blood supply they rely on to grow and spread."
The amazing thing is that we've used the humble yeast, which is a less sophisticated cell than a human cell, to reveal the molecular secrets of the drug and how it works in humans.
The GSAO story
GSAO (glutathionarsenoxide) is an angiogenesis inhibitor drug that "starves" tumour cells by stopping them from making blood vessels -- known as angiogenesis - that tumours rely on to grow and spread. Professor Philip Hogg and Dr Neil Donoghue from the University of New South Wales invented GSAO in 1999.
Because all solid tumours of children and adults, such as cancer of the breast, prostate, colon, lung and brain rely on angiogenesis, a single anti-angiogenic drug should be effective against all tumour types. This is in contrast to chemotherapy drugs and radiotherapy that are often effective only against certain tumour types. Also, because GSAO is not a conventional "cytotoxic" drug that poisons cancer cells, it does not cause unpleasant side effects such as nausea and hair loss.
Small blood vessels consist primarily of endothelial cells that line their interior. They are genetically stable, in contrast to tumour cells that are inherently unstable. Most tumour cells have a propensity for mutation and genetic diversity, and are therefore likely to produce drug resistant cells. The genetic stability of endothelial cells suggests that anti-angiogenic drugs that target the stimulated endothelial cells in tumours will be less prone to resistance than the chemotherapeutic agents that target the tumour cells.
While GSAO would not "cure" people of the cancer, it should stop most types of tumours in their tracks. This means that the focus of cancer treatment and research could move away from curing the disease to one of managing it on a life-long basis, such as diabetes.
GSAO will be first tested in cancer patients in 2006.
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