Cancer Executioner

[Hutch]

I just found this interesting article;

(source) http://news.bbc.co.uk/1/hi/health/5284850.stm

Cancer cell 'executioner' found

Cancer cells keep dividing because the cell suicide process fails
Scientists have developed a way of "executing" cancer cells.
Healthy cells have a built-in process which means they commit suicide if something is wrong, a process which fails in cancer cells.

The University of Illinois team created a synthetic molecule which caused cancer cells to self-destruct.

Cancer experts said the study, in Nature Chemical Biology, offered "exciting possibilities" for new ways of treating the disease.

One of the hallmarks of cancer cells is their resistance to the body's cell suicide signals, which allow them to survive and develop into tumours.

All cells contain a protein called procaspase-3, which the body should be able to turn into caspase-3 - an executioner enzyme.

But this transformation does not happen in cancer cells, even though certain types, such as colon cancer, leukaemia, skin and liver cancers paradoxically have very high levels of procaspase-3.

Healthy cells unaffected

The researchers examined more than 20,000 structurally different synthetic compounds to see if any could trigger procaspase-3 to develop into caspase-3.

They found the molecule PAC-1 did trigger the transformation, and cancer cells from mice and from human tumours could be prompted to self-destruct - a process called apoptosis.

The more procaspase-3 a cancer cell had, the less of the molecule was needed.

Healthy cells, such as white blood cells, were found to be significantly less affected by the addition of PAC-1 because they had much lower levels of procaspase-3, so cell-suicide could not be triggered.

When the scientists tested PAC-1 on cancerous and non-cancerous tissue from the same person, the tumour cells were 2,000-fold more sensitive to PAC-1.

Since different levels of procaspase-3 were found in the cell lines studied, the researchers suggest some patients would be more responsive to this therapy than others, so the it might one day be possible to tailor treatments to individual patients.

'Exciting'

Professor Paul Hergenrother, who led the research, said: "This is the first in what could be a host of organic compounds with the ability to directly activate executioner enzymes.

"The potential effectiveness of compounds such as PAC-1 could be predicted in advance, and patients could be selected for treatment based on the amount of procaspase-3 found in their tumour cells."

Cancer Research UK expert Dr Michael Olson, who is based at the Beatson Institute for Cancer Research in Glasgow, said: "These findings present an exciting new therapeutic strategy for the treatment of some cancers.

"It remains to be seen which, if any tumour types consistently express elevated procaspase-3. That will tell us how many patients could potentially benefit from the drug.

"Clinical trials will be needed to confirm whether procaspase-3 causes any adverse effects in humans."

It has a lot of potential - most cancers are caused not a mutation which causes them to divide uncontrollably but by a mutation cancerous cells which prevent them from committing suicide once this does happen. We'll have to wait another year or two, but this result could be HUGE.

 

[shoowilla]

Many current studies on killing cancer cells have a lot of potential, but dont get your hopes up. Heres an article that was published in The Lancet Oncology in 2000 which is a bit similar

Intracellular fusion antibodies may be suicide for cancer cells

UK scientists have devised a way of killing tumour cells without damaging healthy cells, by generating intracellular antibodies that trigger apoptosis when they specifically bind to antigen.

One novel strategy that promises to improve specificity, and thus reduce toxicity of cancer treatment, is the generation of intracellular antibodies that target oncogene products or chimeric fusion proteins specific to cancer cells. To make this approach more widely applicable and effective, Eric Tse and Terence Rabbitts (MRC Laboratory of Molecular Biology, Cambridge, UK) exploited the ability of caspase-3 – the ‘executioner’ of apoptosis – to self-activate when forcibly dimerised, thus triggering programmed cell death (Proc Natl Acad Sci USA 2000; 97: 12266–71).

John Goldman (Hammersmith Hospital, London, UK) explains the “uniquely ingenious” approach: “The authors have made vectors that express the selected antibody in conjunction with caspase-3, intra-cellularly. When the antibody meets its antigen, the caspase-3 is activated and leads to apoptosis. Therefore, theoretically, the system is totally specific for cells expressing the chosen antigen.” So, says Rabbitts, “the need to target delivery of the vector to tumour cells is obviated”. “Prospective antigens include fusion proteins like BCR-ABL, or mutant proteins like P53 and RAS”, he adds.

As proof of concept, the team used an anti-β-galactosidase antibody fused to caspase-3 in two in vitro systems. By selectively expressing β-galactosidase, they showed that apoptosis was specific for antibody, antigen, and active caspase-3. “Moreover”, the authors note, “the antibody-caspase-3 fusion protein was not toxic to cells in the absence of antigen”. To further reduce the risk of adverse effects, Rabbitts’ group is now modifying the caspase-3 moieties to avoid self-activation without antibody – antigen interaction. In addition, clinical studies will first be done ex vivo, says Rabbitts, with antibodies to BCR and ABL to purge Philadelphia-chromosome-positive cells from the bone marrow of patients with chronic myelogenous leukaemia.

Lucio Luzzatto (Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy) says the approach is attractive because “by using two antigen targets, it has the potential to be highly specific”. However, the main limitation to future clinical effectiveness “is that the procedure would need 100% transduction efficiency in order to destroy a tumour”. Goldman indicates that this may not be essential if the technique is limited to ex vivo purging of bone marrow for autografting. He suggests that other methods, such as alkylating agents and cytotoxic antibodies against cell-surface antigens, might prove simpler, although, counters Rabbitts, these alternative technologies lack specificity and so will not spare healthy cells.

 

[WHITE DEVIL]

It usually takes 10-15 years before a lab study can offer salient results.

Mostly studies, and press releases about studies, are an effort to boost funding for the lab / group who put them on.

 

[2-0-NINE]

If this goes to the Jay Leno Show, they'll probably come up with a Joke saying that "So today, Doctors are trying to make this PS2 a healing thing a ma Jig (LENO LANGUAGE), OR IT'S JUST ANOTHER REASON TO BE LAZY"

 

[Hutch]

The study you are describing was interesting but it was merely proof of concept (the specific words used by the authors of the paper in their conclusion).

This study attempted to produce antibody-caspase 3 hybrids by introducing it into cancer cells through a vector-mediated route. That is never 100% efficient. I try to transform bacterial/yeast cells often, and it is only ever 1-5% efficient (ie. 1-5% of cells contain the vector). All you need is a few cancerous cells which are not transformed and they will soon replicate, rendering it obsolete.

It also requires a direct transformation technique, such as heat-shock or electroporation (shocking the cell walls with electricity, which disrupts the membranes and allows for the uptake of vector DNA). Transformation of the Chinese Hamster Ovary cells used in this study is even more complex, requiring lipofectamine and several other compounds. Performing such transformations in vivo (within the human body) would be almost impossible. Also, it is impossible to differentially transform cancerous cells and normal, healthy cells - they suggest that the antibodies are specific to cancer cells, but the vector containing such products are not. In other words, this vector would target every cell in the body, and only transcribe/translate it's product in cancerous cells.

It will still take almost a decade for use of this synthetic compound to be approved by the FDA (if it ever gets there), and there may still be some nasty side effects that haven't been discovered yet, but out of all of the potential cancer treatments, it is certainly one of the most promising.