Yeast Sheds Light On Promising Anti-Cancer Drug

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Yeast sheds light on promising anti-cancer drug

Category: Cancer/Oncology News

Article Date: 21 Oct 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.

Professor Philip Hogg

p.hogg@...

University of New South Wales

http://www.unsw.edu.au