BOSTON-Susan Band Horwitz, Ph.D., the Falkenstein Professor of Cancer Research and Co-Chair of the Department of Molecular Pharmacology at the Albert Einstein College of Medicine, will today be awarded the 17th annual Warren Alpert Foundation Prize. The foundation recognizes Dr. Horwitz, a molecular pharmacologist, for her seminal contributions to the understanding of how the antitumor agent Taxol inhibits the growth of cancer cells. Her research helped pave the way for studies leading to approval of the plant compound for the treatment of ovarian, breast and lung cancers. The foundation will award Dr. Horwitz a $150,000 prize.
"One thing that Mr. Alpert stipulated when he developed this prize was that it should go to someone who had already made major contributions to helping patients. The impact of Susan's work has been quite extraordinary in the cancer field," said Professor Dominick Purpura, MD, Dean of Albert Einstein College of Medicine, who nominated Dr. Horwitz for the prize. In fact, earlier this year, shortly after Dr. Horwitz was selected as winner of the prize, she was acknowledged by her peers for her contributions to cancer research when she was elected to the National Academy of Sciences.
In the US, Taxol was first approved by the Food and Drug Administration (FDA) for the treatment of refractory ovarian cancer in 1992. Approval for metastatic breast cancer followed in 1994, and more recently for non-small cell lung cancer in 1999. "Taxol has become one of the most valuable cytotoxic chemotherapeutic agents we have in clinical oncology. It has proven effective in ovarian, breast, lung, and head and neck cancer and it has contributed immensely to the quality of life of cancer patients," said Larry Shulman, associate professor of medicine at the Dana-Farber Cancer Institute, Boston. The drug has been used in well over a million patients worldwide.
In 1977, Dr. Horwitz was approached by the National Cancer Institute to study the biological activity of Taxol. In 1966, the compound had been isolated from the bark of the Pacific Yew tree (Taxus brevifolia) as part of a concerted effort to find natural products that might cure cancer. At that time it was shown that Taxol was cytotoxic to cells growing in tissue culture, but over the next ten years there was almost nothing further gleaned about its biological action. However, within a few months of receiving her first samples of the compound, Dr. Horwitz with her then graduate student, Peter Schiff, found that Taxol, which had a unique chemical structure, inhibited cell division , which is deregulated in cancer, thereby promoting uncontrolled cell growth. In subsequent studies she showed that Taxol interferes with mitosis, the process whereby the chromosomes in the nucleus of a cell are duplicated and then segregated equally into two daughter cells.
"Susan's discovery that Taxol bound to and stabilized microtubules, thereby blocking cells in mitosis meant, in fact, that Taxol was a prototype for a new class of chemotherapeutic drugs. Susan recognized this immediately, and it was also quickly sensed by the NCI and others, who then moved Taxol into clinical trials and then pervasive clinical use," said Purpura.
The discovery of Taxol's unique structure and mode of action gave oncologists a new weapon in the fight against cancer. Dr. Horwitz found that unlike many of the cancer drugs that were approved or under development at the time, such as cisplatin and nucleotide analogs that interact with DNA, the mechanism of action of Taxol was not mediated by a direct interaction with DNA. Instead, she found that Taxol interferes with the normal functions of microtubules.
Microtubules are dynamic polymers, hollow cylindrical tubes that are constantly being remodeled by the addition or removal of tubulin subunits. During mitosis, microtubules act like long tethers to pull duplicate chromosomes to opposite poles of the cell so that they can be incorporated into two new nuclei as the cell divides. To complete the process, the microtubules must be shortened as the chromosomes draw near their final destination. Dr. Horwitz reported that Taxol stabilizes microtubules, preventing them from shrinking and therefore blocks the segregation of the chromosomes. It is now known that Taxol perturbs cellular growth at various stages including mitosis, which leads to cellular stress resulting in eventual death. In fact the drug has become a valuable tool in basic cancer research to help delineate the function of microtubules.
Work from Dr. Horwitz's laboratory revealed that Taxol binds specifically to beta-tubulin in the microtubule and causes microtubule bundle formation within the cell. But there are many different types of tubulin in the human body that are expressed in tissue-specific patterns. Today, Dr. Horwitz, who is a past-President of the American Association for Cancer Research (AACR) (2002-2003), continues her work with Taxol, investigating whether the presence of different forms of tubulin might explain why some cancer cells are more responsive to the drug than others. She studies other natural products, from bacteria and marine animals, which have totally different chemical structures from that of Taxol but which bind to microtubules and are functionally similar to Taxol. Such new drugs may offer useful alternatives for Taxol in cases where the drug is poorly tolerated, or ineffective.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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