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Old 02-09-2013, 02:08 PM   #1
gdpawel
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The Role of the Platinum Derivatives in Cancer Therapy

Robert A. Nagourney, M.D.
Rational Therapeutics

The discovery of cisplatinum and the subsequent development of its derivatives (carboplatin and oxaliplatin) represent an interesting saga in modern oncology. When Rosenberg observed in 1960s that platinum electrodes in salt water baths inhibited the growth of bacteria and fungi it lead to the isolation of cis-dichloro diamine platinum (cisplatin). Its application in testicular cancer provided a dramatic leap forward for this heretofore-lethal disease. Subsequent applications in ovary and lung cancers lead to some of the most effective therapies in modern oncology. Although the exact mechanisms of action continue to be investigated, the platination of guanine residues in DNA constitutes the principle mechanism of cytotoxicity.

The use of the human tumor laboratory model has provided us the luxury of exploring the platinum drugs in a wide variety of diseases. Among our published discoveries has been the relative equivalence of the platinum derivatives, as well as their profound synergy with agents like Gemzar (gemcitabine). It is of significant interest that this broadly effective class of compounds extensively applied in the treatment of lung, colorectal, ovarian and breast cancers, as well as others remains less active in the hematologic neoplasms. This is in striking counter distinction to nearly all other classes of chemotherapeutics.

Among our most gratifying observations, from the early 1990s, was the clear and profound activity of the platinum derivatives in breast cancers. We feel that our discoveries, outlined in an editorial published in 2000 (The Once and Future Role of Platinum Agents in Advanced Breast Cancer), in no small part have influenced the broad application of platinum in modern breast cancer management.

It was not genius or divine intervention that lead us to these important discoveries, but, quite simply, the use of a validated human tumor model that accurately probed tumor types, leading us to these findings. It is virtually impossible for an unbiased observer to review these contributions and not recognize that the human tumor model has been the conduit by which these discoveries were made.

The proper study of human cancer is human cancer. Our results speak for themselves when it comes to ovarian, breast and hematologic neoplasms, treatments for which can be traced directly to our laboratories.

http://robertanagourney.files.wordpr...uture-role.pdf
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Old 02-09-2013, 02:09 PM   #2
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How do platinum drugs work?

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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Old 02-09-2013, 02:11 PM   #3
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A Focus on Triple Negative Disease

Robert A. Nagourney, M.D.
Rational Therapeutics

As our understanding of breast cancer biology continues to advance, this disease has come to be understood as many different diseases. Original categorizations based on histology lead to lobular versus ductal subtypes. Thereafter, recognition of estrogen and progesterone status, and finally HER2 status provided further subcategorizations.

Over the past decade, molecular subtypes have characterized this disease into a series of signatures characterized by luminal, basal and other groupings with distinct prognoses. Within the context of these categories, the triple negative breast cancers have emerged as an important target.

These patients whose tumors do not mark for estrogen, progesterone, or HER2 on immunohistochemical or FISH analyses, appear to carry features that segregate them into a BRCA1-like biology. This is of great interest clinically for it offers the opportunity to treat these patients with drugs found active in the BRCA mutant populations.

Among the most active drugs in these patients are the PARP inhibitors. The excellent results with PARP inhibitors and BRCA mutants have been followed by striking response and survival data combining PARP inhibitors with carbo-platinum and gemcitabine. PARP inhibitors by inhibiting DNA damage response can enhance the effects of ionizing radiation, mustard alkylators, topoisomerase inhibitors, platins, and intercalating agents.

We have explored the biology of PARP inhibitors in breast and other cancers. In these investigations, our lab to applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

To date, we have observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients, and in some triple negative patients. More interesting, will be the results combining the PARP inhibitors with mustard alkylators, platins, and drug combinations to optimize PARP inhibitor combinations.

This work is ongoing in triple negative and BRCA positive patients as well as other tumor types where the PARP inhibitors may prove useful in the future.

PARP Inhibitiors in Breast Cancer

http://cancerfocus.org/forum/showthread.php?t=3383
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