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Old 05-07-2007, 11:06 AM
Dross Dross is offline
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Default Diabetes drug dramatically boosts power of platinum chemotherapy

A widely used diabetes drug dramatically boosted the potency of platinum-based cancer drugs when administered together to a variety of cancer cell lines and to mice with tumors, scientists from Dana-Farber Cancer Institute report.

Combining a platinum chemotherapy agent and the diabetes drug Avandia (rosiglitazone) halted or shrank mouse tumors as much as three times more effectively than either of the drugs given alone, according to the article in the May issue of Cancer Cell.

If pairing the drugs has the same synergistic effect in humans, the researchers say, it could improve control of ovarian, lung and other cancers routinely treated with platinum-based chemotherapy, to which tumors eventually become resistant. Moreover, the experiments suggest the combination might extend the use of platinum drugs to other cancers where they haven't previously been shown to be effective.

"There's still a huge gulf between these experiments and human cancers," said Bruce Spiegelman, PhD, senior author of the report. "But it's worked in every animal model of cancer we've looked at, and I think there's a fair chance it will help people."

Dana-Farber researchers are already drawing up plans for initial clinical trials, which could begin sometime this year.

"We really see a way forward here to improve the chemotherapy's effectiveness for multiple forms of cancer," said George Demetri, MD, a Dana-Farber researcher who is preparing a proposal for a pilot study of Avandia (rosizitaglone) and platinum chemotherapy drugs in lung and ovarian cancer and sarcomas.

If a pilot study shows promising activity, the combination would need to be compared with standard chemotherapy in larger phase 2 and phase 3 trials involving many hundreds of patients.

Avandia (rosizitaglone) enhances insulin receptors' sensitivity in diabetics whose pancreas secretes too little insulin. It was approved in 1999 for use by patients with type 2 diabetes to help control blood sugar levels. An estimated 5 million people in the U.S. take Avandia or a similar drug, piozitaglone, which is sold as Actos.

Both drugs work by activating PPAR-gamma, a transcription factor that functions as a master regulator of fat development in the body, a function discovered in the Spiegelman lab in 1994. Spiegelman and others observed that certain PPAR-gamma-activating compounds, called PPAR-gamma ligands, caused cancer cells to stop growing and become more mature, or differentiated.

Therefore, Spiegelman and others felt it was a logical step to try PPAR-gamma ligands as cancer treatment, but several small clinical trials found rosiglitazone alone was ineffective against several cancer types.

Despite this setback, and because Avandia (rosizitaglone) was well-tolerated by patients compared to standard cancer drugs, Dana-Farber researchers believed it was worthwhile to try it and similar PPAR-gamma ligands in a different context, said Geoffrey Girnun, PhD, a researcher in Spiegelman's laboratory and lead author of the Cancer Cell report. "After discussing it with other Dana-Farber researchers, we decided to try these agents in combination with platinum-based drugs, and in several different cell lines, we saw positive results," said Girnun.

In addition to Avandia (rosizitaglone), the scientists tested Actos (pioglitazone) and an experimental compound made by Glaxo Smith Kline, combining each of them with cisplatin, carboplatin and oxalyplatin -- all commonly used chemotherapy drugs that destroy cancer cells by damaging their DNA.

When non small-cell lung cancer cell lines were treated with Actos (rosizitaglone) alone, there was no effect on growth. Carboplatin alone reduced growth of the cancer cells by about 60 percent. But when both drugs were administered, cell growth was reduced by 80 percent. The drugs were also tested individually and together on ovarian cancer cell lines that normally are resistant to chemotherapy -- and proved capable of reducing growth of the cancer cells by 90 percent.

Even when applied to colon cancer cells, a type of cancer not usually treated with platinum drugs, Actos (rosiglitazone) and carboplatin lowered the growth rate by 70 percent. (Rosizitaglone did not show the same positive effect when paired with oxalyplatin.)

The drug combination also had striking growth-suppressing results when given to mice with human lung and ovarian tumors implanted under their skin and in mice that had received a chemical that causes them to develop colon cancer, explained Spiegelman, who is also a professor of cell biology at Harvard Medical School.

The experiments showed that the PPAR-gamma ligands suppressed the activity of metallothioneine genes, which are believed to trigger the development of cancer cells resistance to platinum chemotherapy.

"Our finding that PPAR-gamma activation dramatically increases the efficacy of carboplatin, potentially causing tumor stasis or even tumor shrinkage could represent a significant advance in chemotherapy," the researchers wrote.

Last edited by gdpawel : 05-11-2012 at 05:58 PM. Reason: post full article
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Old 07-17-2012, 09:39 AM
gdpawel gdpawel is offline
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Default Another platinum drug to boosts power of platinum chemotherapy

Researchers at Massachusetts Institute of Technology (MIT) in the US who are testing phenanthriplatin, a new experimental drug based on platinum, say it kills cancer cells better and may provide a more effective alternative to cisplatin, the most commonly used approved platinum chemotherapy drug.

Platinum-based chemotherapy drugs are among the most powerful and widely used against cancer. However, they have toxic side effects, and tumors can become resistant to them.

Cisplatin, the most common platinum chemotherapy drug, was first approved in the US in 1978. It is particularly effective against testicular cancer, and is also used in the treatment of ovarian and some lung cancers, as well as lymphoma and other cancers.

In a paper published in the Proceedings of the National Academy of Sciences (PNAS), senior author Stephen J Lippard and colleagues suggest phenanthriplatin not only kills cancer cells better than cisplatin, but it may also evade cancer-cell resistance to conventional platinum-based drugs.

Lippard, a professor of chemisty, has been studying platinum drugs for a long time. He told the press he had long believed platinum was special in its ability to deal with cancer. Now, using new variants, "we might have a chance of applying platinum to a broader range of cancer types, more successfully," he said.

One reason that phenanthriplatin appears to be more effective than cisplatin is that it can get into cancer cells more easily. Another reason is that it inhibits transcription, the first step of gene expression, where cells convert DNA to RNA.

Platinum-based drugs are effective against cancer because at their centre is a platinum atom joined to two ammonion molecules and two chloride ions. The compound is negatively charged, but when it enters the cancer cell it becomes positively charged because the chloride ions are replaced by water molecules.

The water molecules are easily displaced, allowing the platinum-based compound to attach to DNA in the cancer cell: it forms cross-links in the DNA that block the cell's ability to read the code, which is essential for cell function. If enough of the DNA is unreadable, the cell dies. This is how cisplatin works.

At first, it was thought that only compounds with two DNA binding sites (the two chlorine ions that are replaced by water) would be effective against cancer cells, because it was the ability to form cross links that mattered. But around the 1980s, scientists began to discover some positively-charged platinum compounds that can only bind to DNA at one site also have anti-cancer properties, and so they became interesting again.

For some time, Lippard and his group have been experimenting with different platinum compounds and looking at this underlying mechanism. They want to find similar drugs that could be more powerful, work against more types of cancer, plus have fewer side effects and evade cancer-cell resistance.

In 2008, they looked at pyriplatin, which is similar to cisplatin, except one of the chlorine atoms is replaced by a six-membered pyridine ring containing five carbon atoms and one nitrogen atom. But when they tested it, it was not as powerful in killing cancer cells as as cisplatin or oxaliplatin, another FDA-approved platinum-based cancer drug.

But it got them thinking, and they set off looking for similar compounds with larger rings; plus they had a hunch larger rings would make the drug more effective at blocking DNA transcription. And that's how they came across phenanthriplatin.

In tests using 60 types of cancer cell, phenanthriplatin was between 4 and 40 times more powerful than cisplatin, depending on the cancer type. And, due its different pattern of activity, the researchers suggest it could be effective against cancer types that cisplatin is no good for.

When faced with cisplatin, some cancer cells are able to establish defences and develop resistance to the drug. The cells contain sulfur compounds such as glutathione that attack the platinum and destroy it before it can reach and bind to DNA.

The researchers found phenanthriplatin appears to evade some of these defences because its bulky three-ring attachment seems to stop the sulfur from mounting such a powerful attack on the platinum. "... it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance," they write.

Luigi Marzilli, a professor of chemistry at Louisiana State University, was not involved in the study. He said phenanthriplatin shows promise as a new cancer treatment because:

"It expands the utility of platinum drugs and avoids some of the problems that existing drugs have."

Lippard and colleagues are now doing animal tests to find out how the drug spreads in the body and how well it kills tumors in the body as opposed to cells in a test tube. Lippard says they may be able to modify the compound to improve those properties.

References: "Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile"; Ga Young Park, Justin J. Wilson, Ying Song, and Stephen J. Lippard; PNAS published ahead of print 6 July 2012; DOI:10.1073/pnas.1207670109

[url]http://www.pnas.org/content/early/2012/07/05/1207670109.abstract

Catharine Paddock PhD. "New Platinum Drug Kills Cancer Cells Better." Medical News Today. MediLexicon, Intl., 17 Jul. 2012.
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Old 07-27-2012, 01:26 AM
gdpawel gdpawel is offline
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Default How cisplatin reaches the nucleus

Platinum complexes such as the well-known cisplatin are powerful antitumor medications. They cross the cell membrane and reach the nucleus, where they attach to DNA and stop cell growth. But how does cisplatin get to the nucleus? Italian researchers have now proven that a copper transport protein may play a critical role. In the journal Angewandte Chemie, they present their hypothesis about the transport mechanism.

It has always been assumed that cisplatin simply passes through the cell membrane; however, growing evidence indicates that a copper transporter is involved. Ctr1 is a membrane-dwelling protein that brings copper into cells. It consists of three helical segments that sit in the membrane, one end protruding into the cell, the other on the outside. Three such molecules lodge together to form a channel-like structure. The end that sticks out of the cell and the interior of the channel contain many sulfur-containing methionine groups, which are important for binding copper.

A team led by Giovanni Natile at the University of Bari (Italy) has now proven that this structural element also plays a role in binding platinum. The researchers produced a synthetic peptide with a structure very similar to the extracellular end of the copper transport protein. Cisplatin is a complex with a central platinum ion and four ligands: two neighboring amino groups and two neighboring chloride ions. The peptide displaces all four of these ligands and binds to the platinum ion itself.

As is the case for copper, the transport protein seems to bind the platinum atom from cisplatin by replacing all other ligands bound to the metal ion. The next step could be the traversal of a ligand-free naked platinum atom through the channel and into the cytosol of the cell. However, this contradicts other experiments that have demonstrated that treated tumor cells do not contain bare platinum, but rather undegraded cisplatin accumulated in certain organelles.

Natile and his co-workers have proposed an interesting hypothesis to explain these observations: After an initial interaction between a few cisplatin molecules and the methionine-rich extracellular end of the copper transporter, the platinum ion does not pass through the channel, but instead stabilizes the trimeric channel structure. This sets in motion a mechanism called endocytosis, in which the cell membrane encircles the transporter and forms a little interior bubble filled with the outer medium. This medium contains some intact cisplatin. The bubble then migrates to the interior of the cell and comes into contact with the organelles, including the nucleus.

Platinum-based drugs are effective against cancer because at their centre is a platinum atom joined to two ammonion molecules and two chloride ions. The compound is negatively charged, but when it enters the cancer cell it becomes positively charged because the chloride ions are replaced by water molecules.

The water molecules are easily displaced, allowing the platinum-based compound to attach to DNA in the cancer cell: it forms cross-links in the DNA that block the cell's ability to read the code, which is essential for cell function. If enough of the DNA is unreadable, the cell dies.

Platinum-based chemotherapy drugs are among the most powerful and widely used against cancer. However, they have toxic side effects, and tumors can become resistant to them.

When faced with a platinum drug, some cancer cells are able to establish defenses and develop resistance to the drug. The cells contain sulfur compounds such as glutathione that attack the platinum and destroy it before it can reach and bind to DNA.

Massachusetts Institute of Technology
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Last edited by gdpawel : 02-16-2013 at 07:05 PM. Reason: additional info
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Old 11-18-2012, 02:02 AM
gdpawel gdpawel is offline
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Default Can dietary methionine restriction increase the effectiveness of chemotherapy?

J Am Coll Nutr. 2001 Oct;20(5 Suppl):443S-449S; discussion 473S-475S.

Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer?

Epner DE, Baylor College of Medicine, Houston, Texas, USA. [email]depner@bcm.tmc.edu

Abstract

Most metastatic tumors, such as those originating in the prostate, lung, and gastrointestinal tract, respond poorly to conventional chemotherapy. Novel treatment strategies for advanced cancer are therefore desperately needed. Dietary restriction of the essential amino acid methionine offers promise as such a strategy, either alone or in combination with chemotherapy or other treatments. Numerous in vitro and animal studies demonstrate the effectiveness of dietary methionine restriction in inhibiting growth and eventually causing death of cancer cells. In contrast, normal host tissues are relatively resistant to methionine restriction. These preclinical observations led to a phase I clinical trial of dietary methionine restriction for adults with advanced cancer. Preliminary findings from this trial indicate that dietary methionine restriction is safe and feasible for the treatment of patients with advanced cancer. In addition, the trial has yielded some preliminary evidence of antitumor activity. One patient with hormone-independent prostate cancer experienced a 25% reduction in serum prostate-specific antigen (PSA) after 12 weeks on the diet, and a second patient with renal cell cancer experienced an objective radiographic response. The possibility that methionine restriction may act synergistically with other cancer treatments such as chemotherapy is being explored. Findings to date support further investigation of dietary methionine restriction as a novel treatment strategy for advanced cancer.

[url]http://www.ncbi.nlm.nih.gov/pubmed/11603655
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Old 11-23-2012, 06:17 PM
gdpawel gdpawel is offline
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Default Copper Depletion Therapy Very Effective At Preventing Spread Of Cancer

Copper depletion therapy has shown surprisingly good results in preventing the spread of cancer to organs in high-risk triple-negative breast cancer - a form of cancer that is very difficult to treat.

A study, carried out by researchers at Weill Cornell Medical College and published in the Annals of Oncology, found that copper depletion treatment has the ability to successfully prevent organs from receiving migrating cancer tumor cells - putting a stop to the spread of tumors.

The average survival time is 9 months for patients suffering from metastatic triple-negative breast cancer. However, the study found that patients who were at high risk of cancer recurrence and received copper depletion therapy - in the form of the drug tetrathiomolybdate (TM) - experienced an overall increase in survival time as well as a decreased risk of relapse.

The clinical trial began in 2007 and included 60 patients, of whom more fifty percent suffered from triple-negative breast cancer. However, the research from this report only looked at the first 40 patients involved in the study.

Only two of 11 participants who had a history of advanced triple-negative breast cancer relapsed within 10 months of being treated with TM. In addition, four of the participants experienced long-term benefits, living cancer free for between three and five and a half years.

According to the senior investigator of the study and director of the Breast Cancer Research Program, Dr. Linda Vahdat: "These study findings are very promising and potentially a very exciting advance in our efforts to help women who are at the highest risk of recurrence.

The anti-copper compound appears to be keeping tumors that want to spread in a dormant state. We believe one of the important ways it works is by affecting the tumor microenvironment, specifically the bone marrow-derived cells that are critical for metastasis progression."

The progression-free survival rate among 29 patients with other forms of high-risk for relapse - such as stage 4 or stage 4 breast cancer - was also surprisingly good (at 85 percent to date).

However, Dr. Vahdat notes that the benefits of TM treatment can't be fully appraised until it's compared with other forms of therapy.
Copper depletion preventing cancer from spreading

Recent breakthroughs in the science of metastasis have improved our understanding of exactly how and why the human body uses copper - and the role it plays in the spread of cancers.

Researchers from Weill Cornell identified the important role bone marrow cells - in particular VEGFR1+ hematopoietic progenitor cells (HPCs) - play in metastasis. Studies show that they are responsible for preparing special sites in organs that accept and nurture migrating cancer cells, as well as inviting Endothelial progenitor cells (EPCs) which feed the cancerous cells.

Immediately before cancer relapse, the levels of EPCs and HPCs significantly increase. This indicates that targeting EPCs with copper depletion is viable. Copper is one of the key components of enzymes that control tumor microenvironment, as well as appearing to have a role in how cancer cells migrate.

Depleting copper decreases proliferation of EPCs.

Dr. Vahdat concludes: "Breast tumors want to move to specific organs, and these EPCs and HPCs cells leave a 'popcorn trail' for cancer cells to follow, as well as provide the building blocks for blood vessels to greet them as they arrive.

There are a lot of cancer experts at Weill Cornell working very hard to understand this precise mechanism, define the clinical benefit in this ongoing copper depletion drug clinical trial, and determine its future study. Keeping cancer dormant is what we all want for our patients -- especially triple-negative breast cancer patients at highest risk of recurrence."

References:

"Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse" S. Jain1, J. Cohen, M. M. Ward, N. Kornhauser, E. Chuang, T. Cigler, A. Moore, D. Donovan, C. Lam, M. V. Cobham, S. Schneider, S. M. Hurtado Rúa, S. Benkert, C. Mathijsen Greenwood, R. Zelkowitz, J. D. Warren, M. E. Lane, V. Mittal, S. Rafii and L. T. Vahdat

Annals of Oncology

Citation: Joseph Nordqvist. "Copper Depletion Therapy Very Effective At Preventing Spread Of Cancer." Medical News Today. MediLexicon, Intl., 16 Feb. 2013

[url]http://annonc.oxfordjournals.org/content/early/2013/02/04/annonc.mds654.abstract?sid=b135fa2d-5d8a-42b4-bfc4-e86d15d8eca0
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