Super-sizing a cancer drug minimizes side effects

Jul 28, 2010
Crystals of cisplatin, a platinum compound that is used as a chemotherapy drug, are shown here Image: National Cancer Institute

One of the first chemotherapy drugs given to patients diagnosed with cancer — especially lung, ovarian or breast cancer — is cisplatin, a platinum-containing compound that gums up tumor cells’ DNA. Cisplatin does a good job of killing those tumor cells, but it can also seriously damage the kidneys, which receive high doses of cisplatin because they filter the blood.

Now a team of scientists at the Harvard-MIT Division of Health Sciences and Technology (HST) has come up with a new way to package cisplatin into that are too big to enter the kidneys. The new compound could spare patients the usual side effects and allow doctors to administer higher doses of the drug, says Shiladitya Sengupta, leader of the research team.

“We could give so much more cisplatin than is now possible,” says Sengupta, an assistant professor of HST. “You could wipe out the tumor by carpet-bombing it.”

Tumors in mice treated with the new cisplatin nanoparticle shrank to half the size of those treated with traditional cisplatin, with minimal side effects. The findings were reported in the Proceedings of the National Academy of Sciences in June.

Beads on a string

Doctors began using cisplatin to treat cancer in the 1970s. Early on, doctors recognized that it harmed the kidneys, and cancer researchers began looking for alternatives. In the past few decades, the FDA has approved two less-toxic derivatives of cisplatin: carboplatin and oxaliplatin. However, those drugs don’t kill tumor cells as successfully as cisplatin.

Cisplatin’s effectiveness lies in how easily it releases its platinum molecule, freeing it to cross-link DNA strands, disrupting cell division and forcing the cell to undergo suicide. Carboplatin and oxaliplatin are less effective (but less toxic) than cisplatin because they hold on to their platinum atoms more tightly.

Sengupta and his colleagues took a new approach to making cisplatin safer: stringing cisplatin molecules together into a nanoparticle that is too large to get into the kidneys. (It has been shown that the kidneys cannot absorb particles larger than five nanometers — about 1/10,000th the diameter of a human hair).

His team designed a polymer that binds to cisplatin, arranging the molecules like beads on a string. The string then winds itself into a nanoparticle about 100 nanometers long — much too large to fit into the kidneys. However, the particles can still reach tumor cells because tumors are surrounded by “leaky” blood vessels, which have 500-nanometer pores.

Their first nanoparticle proved less effective than cisplatin, so they tweaked the polymer to make it hold a little less tightly to platinum, and ended up with a molecule with a tumor-killing power similar to cisplatin’s. However, because its side effects are minimal, the nanoparticle can be delivered in higher doses.

Daniela Dinulescu, an author of the paper and pathology instructor at Brigham and Women’s Hospital in Boston, showed that the nanoparticles outperformed cisplatin in mice engineered to develop ovarian cancer. The researchers also showed it to be effective against lung and breast tumor cells grown in the lab. Once the die, the immune system clears platinum from the body.

It is difficult to develop and gain approval for new platinum-based compounds, says Nicholas Farrell, professor of inorganic chemistry at Virginia Commonwealth University, but he believes Sengupta’s new nanoparticles are promising. “If successful, the approach promises to maintain the status of cisplatin as one of the most useful drugs available to the clinician,” says Farrell.

The MIT researchers are now working on new variants of the nanoparticles that would be easier to manufacture. They are also making plans to test the nanoparticles in clinical trials, which Sengupta hopes will get underway within the next two years. The polymer used for the nanoparticle backbone is similar to malic acid, a natural product of cellular metabolism, so Sengupta is optimistic that it will prove safe in humans.

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User comments : 9

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kshultz222_yahoo_com
3 / 5 (2) Jul 28, 2010
Start clinical trials in two years?!? That is a joke. Next week would be too long to wait.
fixer
1 / 5 (1) Jul 28, 2010
If it's not available now it's an advert.
If you need a cure now try typing "cancer cure" into google.
If you don't see anything you like, try here!
http://www.physor...379.html
trekgeek1
5 / 5 (1) Jul 28, 2010
If someone is terminal and has a near zero chance of survival, why can't they sign a waiver and try it now? How much further would we be if we let terminal patients try new medical treatments instantly instead of waiting years?
KronosDeret
5 / 5 (1) Jul 29, 2010
i agree with trekgeek1, well kinda. anyone in medical field took an oath that he will lower suffering. medical trials on terminal patients is probably one of the most controversial things ever. You simply cannot predict if the test subject would not suffer much more.
fixer
1 / 5 (1) Jul 29, 2010
You won't find a doctor that puts the patients interests before his own.
Any one who is terminal reading this article will be long dead before the product becomes available.
These articles are heartless and offensive, Physorg editors need to show some responsibility and think before advertising therapies that may never become available.
frajo
not rated yet Jul 30, 2010
If it's not available now it's an advert.
If you need a cure now try typing "cancer cure" into google.
If you don't see anything you like, try here!
http://www.physor...379.html
You better read first the comments on http://www.physor...671.html . Some people are not the experts they pretend to be.
frajo
not rated yet Jul 30, 2010
Start clinical trials in two years?!? That is a joke. Next week would be too long to wait.
No objection, if it's for yourself. But if you're a pharma producer proponent you'd be acting irresponsible.
Remember thalidomide?
fixer
not rated yet Jul 30, 2010
@frajo
I remember thalidomide, terrible drug now resurfacing for a different therapy.
I agree with your comment on experts, so I speak only from personal experience.
I spent weeks researching every aspect of both M.P. and A.R.T.before commiting, none of which would have been necessary had my doctor taken the same trouble!
For info, Artemisinin first isolated 1972, classified by the FDA as a harmless food suplement but the W.H.O,s drug of choice for malaria and saves about 1m lives every year.
Currently undergoing clinical trials in Germany as 1st choice anticancer drug.

Marshall Protocol, first developed 2000 and still saving lives, currently undergoing clinical trials at west China hospital as 1st choice for Ankylosing Spondylitis.
But why take my word for it? you have a computer and time to post so try a bit of cut and paste in Google.

No need to reinvent the wheel, It's all available already for those who take the trouble to look.
Good hunting!
frajo
not rated yet Jul 30, 2010
For info, Artemisinin first isolated 1972, classified by the FDA as a harmless food suplement but the W.H.O,s drug of choice for malaria
Wikipedia:
The World Health Organization is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large
and saves about 1m lives every year.
Currently undergoing clinical trials in Germany as 1st choice anticancer drug.
The German wiki page says:
Die Pruefung des Artemisinins als potentielles Krebsmedikament befindet sich noch in einem fruehen Stadium.
Obviously, you are confusing "fruehes Stadium" (early phase) with "1st choice".
And obviously you don't understand that cancer is not one disease but a family of diseases for which there will be no common "1st choice anticancer" drug in the foreseeable future.