Garlic “Smart Bomb”

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Prof. David Mirelman. Garlic compund kills cancer

 

Weizmann Institute scientists have destroyed malignant tumors in mice using a chemical that occurs naturally in garlic. The key to the scientists’ success lies in the development of a two-step system that delivers the cancer-treating chemical directly to the tumor.


The active chemical, called allicin, is the substance that gives garlic its distinctive aroma and flavor. For many years, scientists studying allicin have known that it is as toxic as it is pungent. It has been shown to kill not only cancer cells, but the cells of disease-causing microbes and even healthy human body cells. Fortunately for our cells, allicin is highly unstable and breaks down quickly once ingested. However, its rapid breakdown and undiscriminating toxicity have presented twin hurdles to creating an effective allicin-based therapy. 


Researchers in the Institute’s Biological Chemistry Department have now solved this double challenge, designing a delivery method that works with the pinpoint accuracy of a smart bomb. The study, reported in Molecular Cancer Therapeutics, was performed by Drs. Aharon Rabinkov, Talia Miron and Marina Mironchick, working with Profs. David Mirelman and Meir Wilchek.


Allicin is not present in unbroken cloves of garlic; it is produced in a biochemical reaction between two substances stored apart in tiny adjoining compartments within each clove - an enzyme called alliinase and a normally inert chemical called alliin. When the clove is damaged - whether by food-seeking soil parasites or upon crushing in cooking - the membranes separating the compartments are ruptured, alliin and alliinase interact, and allicin is produced.


The scientists wondered whether it might be possible to reproduce this natural reaction at the site of a tumor. In this way, toxic allicin molecules could be aimed directly at the cancer cells.


To pursue this goal, the scientists took advantage of the fact that most types of cancer cells exhibit distinctive receptors on their surfaces. They took an antibody naturally programmed to recognize one of these receptors and chemically bonded it to the garlic enzyme, alliinase. They then injected this paired unit into the bloodstream, where, as expected, it proceeded to seek out cancerous cells. The second component, alliin, was then injected at intervals. When encountering the alliinase enzyme, the normally inert alliin molecules were turned into lethal allicin molecules, which then penetrated and killed the tumor cells. Neighboring healthy cells remained intact due to the precise delivery system.


Using this method, the team has succeeded in blocking the growth of gastric tumors in mice. The tumor-inhibiting effects were seen up to the end of the experimental period, long after the internally produced allicin was spent. The scientists note that the method could work for most types of cancer, as long as a specific antibody could be customized to recognize receptors unique to the particular cancer cell. The technique could prove invaluable for preventing metastasis following surgery. “Even though doctors cannot detect where metastatic cells have migrated and lodged themselves,” says Mirelman, “the antibody-alliinase unit should be able to hunt them down and, in the presence of alliin, destroy them anywhere in the body.”

 

Cancer cells -- before and after allicin treatment

 

From vampires to fungi


Long hailed as a wonder plant, garlic has been used traditionally for everything from warding off vampires to treating bacterial and fungal infections. The ancient Egyptians fed garlic to their pyramid-building slaves to enhance their stamina; the Greeks used it to treat bladder infections, leprosy and asthma; and in World War I, following research by Louis Pasteur proving garlic’s anti-bacterial properties, the plant was used to disinfect open wounds and prevent gangrene.


Modern research has confirmed that garlic has antibacterial, antiviral, antifungal, anti-amoebic, anti-inflammatory and even heart-protecting properties, with a lipid-lowering effect that prevents the accumulation of fatty deposits. Allicin, the active compound in crushed garlic, has been shown to kill over 20 types of bacteria, including Salmonella and Staphylococcus.


In previous research, Prof. Mirelman and his colleagues Dr. Miron, Dr. Rabinkov and Prof. Wilchek revealed that allicin kills disease-causing amoebas, bacteria and fungi by inactivating some of their enzymes. This finding led to current efforts to develop therapies against intestinal and fungal diseases, which claim the lives of thousands yearly and afflict millions more. The group has also shown that allicin can function as an antioxidant, inactivating harmful oxygen molecules believed to contribute to atherosclerosis.

Alliin and Alliinase combine to form cancer-killing allicin

 

 

 
Prof. David Mirelman. On target
Life Sciences
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Cancer Fights Back

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Prof. Gideon Berke. Mounting the attack
 
 

 

It's war. And it's not just "out there,"but inside our bodies, where a fleet of immune agents is constantly on the lookout for rogue invaders -  viruses, bacteria, and fungi. Over the past few decades, as scientists have tirelessly traced the micro-trenches of our body's battle zones, scoring increasingly promising victories in the form of antibiotics, vaccines, and even the anti-AIDS-virus cocktail, hopes have risen that one day we may also succeed intargeting foes from within, such as cancerous tumors.

"One of the most compelling questions is why the body is unable to mount an effective attack against its aberrant cells," says veteran immunologist Prof. Gideon Berke of the Weizmann Institute of Science. "The puzzle is that the immune system actually starts by generating a potentially promising response -  namely, killer cells that can seek out and destroy a tumor. Yet within a short time these cells all but disappear while the tumor marches on."

Berke specializes in white blood cells known as cytolytic T lymphocytes (CTLs), ingenious killer cells present in nearly every organ. Lining his office walls are volumes of publications dating back to the late 1960s, when he was a graduate student working with Haim Ginzburg. They were the first to discover the in vitro generation of killer cells and to analyze specific details of their killing activity. The 70s, 80s, and early 90s found him and scores of scientists worldwide striving to determine the T-cell's molecular mode of action in greater detail.

These efforts led to the surprising, and perhaps frustrating, finding that in parallel to the T-cells'attack on them, cancer cells are able to mount a counterattack. Furthermore, they use the very same weapon employed by T-cells -  a mechanism first proposed by Berke and others back in the early 90s (see box). The key is a lethal interaction between a molecule called FasL, present on the attacking cell, and a death receptor on the target cell named Fas. Upon activation the Fas receptor triggers a built-in cell suicide mechanism known asapoptosis.

The discovery that tumor cells, like T-cells, also use FasL in self-defense stirred immense excitement. "It was surprising, clever, elegant,"says Berke. But then conflicting evidence started to emerge, including the finding of tumors that did not express FasL and the fact that there was often no difference between the fates of patients expressing FasL and those who did not.


T-cell fratricide


Berke and his colleagues have now shed light on this puzzle using in vivo-induced killer cells. In a study recently published in Immunology, the team, including graduate student Jie-Hui Li and Dr. Dalia Rosen, together with Prof. Paul Sondel of the University of Wisconsin, here on sabbatical at the time, confirmed that both tumors and killer T-cells are endowed with FasL and Fas receptors. Each "camp"is able to kill the other, yet tumors seem to have the upper hand. They can also cause T-cells to turn on one another, killing other cancer-fighting T-cells as well as innocent bystanders (see diagram).

These insights into cell death induced by tumor/immune skirmishes are already influencing clinical oncology. One new approach aims atdetermining a patient's prognosis or optimal treatment based on the presence or absence of FasL and Fas in cancerous cells. In related research, Berke is developing a test to determine tumor sensitivity to existing cancer drugs, relying on afluorescent dye that labels cells undergoing cell death following exposure to a drug. The test has so far proven successful in gauging the susceptibility of breast and colon cancer tissue to different drugs.

T-cell death scenarios

 

Raining winning ideas


Looking out the window of his bus en route to a meeting in Cambridge, many years ago, Berke was suddenly struck with an idea that would later become a leading thread in his scientific thinking. "It was a rainy September day,"he recalls, "and the fields were a gloomy yellow."Having grown up in Israel, Berke was used to dust-colored summer fields hungry for rain, but it seemed highly curious in England, where it was raining cats and dogs. "The idea suddenly came to me that there must be a genetic programming that makes plants die even when they have sufficient nutrients and water,"says Berke. "They die because they are supposed to."

In 1991, this idea of an in-built cell-death mechanism led Berke to propose a new theory of how killer T-cells target their foes, challenging the then-prevalent hypothesis championed by Pierre Henkart of the U.S. National Institutes of Health. Henkart had suggested that T-cells kill by releasing substances that perforate the target cell membrane. These perforations then enable certain enzymes to penetrate the target cell, causing DNA fragmentation and apoptosis.

The trouble was that Berke and electron microscopy expert Dr. Dalia Rosen, working with certain killer cells, couldn't find any evidence supporting either the presence of these enzymes or the formation of membrane lesions. Concluding that an alternative pathway must exist, they proposed that killer cells function by activating built-in receptors in the target cell, which in turn trigger the cell's demise. This theory later proved right on the mark when researchers in France and Japan discovered the cell's FasL / Fas apparatus.


Tumor tactics


Masters of deceit, cancer cells employ a variety of schemes to outwit the immune system. These include:

·          Counterattack: The tumor fights back, suppressing the immune response.

·           Camouflage: Variants of the tumor are created, lacking the features that would mark them for destruction.

·          Sidestepping: The tumor deflects the immune attack by producing anti-apoptotic proteins that neutralize the immune cells'weaponry.

 
Prof. Berke holds the Isaac and Elsa Bourla Chair in Cancer Research.
 
 
 
Prof. Gideon Berke.
Life Sciences
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Death of a Cell

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Dr. Atan Gross. Rules of cell suicide
 

 

 
 
The basic units of all living organisms can travel two main paths on their final journey. One is a form of self-sacrifice. Cell suicide, 'apoptosis,' occurs when cells have become potentially harmful or unnecessary. 'The kill is fast and tidy,' says Dr. Atan Gross of the Weizmann Institute's Biological Regulation Department. 'There are no leftovers, no inflammation, and no harm to surrounding cells.' The cell shrinks, dies, and is then eaten by other cells. Failure of this mechanism can lead to illnesses such as cancer, AIDS, or Alzheimer's disease.

But self-destruction doesn't come easy. A cell's self-destruction manual contains a complex set of instructions, which scientists have long struggled to decipher. In the 1980s, the discovery of a family of proteins called BCL-2, which plays a major role in apoptosis, transformed the field from an apparent impasse to one that might, with difficulty, be traversed. Research received a major boost when enzymes called caspases were found to also serve as activators of certain BCL-2 family members. The field was finally stimulated into what it is today - a focal point for cancer research, teeming with scientists who seek to solve this as yet undecipherable riddle.

Gross's team is conducting three separate studies related to apoptosis. Two deal with how the powerhouse of the cell, the mitochondrion, is involved in apoptosis. Scientists feel that understanding how the mitochondrion breaks apart in apoptosis is crucial to understanding cell suicide. Some believe that channels in the mitochondrion form during the process, and that the mitochondrion's innards leak through them. Other theories point to the formation of oxygen radicals as causing the rupture of the mitochondrion's membrane.

Most recently, Gross found that before apoptosis, a version of a molecule in the BCL-2 family, called tBID, forms aggregates in the mitochondrion's membrane, possibly in an effort to construct channels.

Hoping to explore this phenomenon further, Gross decided to check what happens when BAX, another molecule belonging to the BCL-2 family, is introduced into yeast. 'As a single-celled organism, yeast lacks its own apoptotic mechanism, thus offering an ideal control setting for selectively examining the effect of specific molecules on apoptosis,' explains Gross, adding that its single-celled status also makes it easy to manipulate.

An additional study, which Gross conducted in collaboration with Prof. Alex Tsafriri of the same department, deals with apoptosis in the ovary (atresia). Gross: 'Apoptosis is crucial to ovulation. Ovaries contain huge numbers of follicles, carrying immature eggs, of which thousands undergo atresia. Follicles that reach the ovulation stage are the exception to the rule.' Observing follicles in culture, he found that caspases were barely activated in apoptosis, and apoptosis still occurred when caspase activity was inhibited. On the other hand, when ovulation was induced, caspase activity, surprisingly, increased. Caspases, then, may play a non-apoptotic role in the ovulation process.

As Gross and other scientists work to unlock the secrets of apoptosis, one can only hope that new understandings in the field will lead to improved treatment of some of humankind's most menacing diseases.

Dr. Gross holds the Robert Armour Family Career Development Chair in Perpetuity. His research is supported by Mr. and Mrs. Stanley Chais, Beverly Hills, CA; the Dolfi and Lola Ebner Center for Biomedical Research; the Y. Leon Benoziyo Institute for Molecular Medicine; the Willner Family Center for Vascular Biology; Mr. and Mrs. Bram of Belgium; the Louis Chor Memorial Trust Fund; the Harry and Jeanette Weinberg Fund for Molecular Genetics of Cancer; Yad Hanadiv; the Jean-Jacques Brunschwig Fund for the Molecular Genetics of Cancer; and the Foundatin Fernande et Jean Gaj.
 
 
Dr. Atan Gross.
Life Sciences
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light therapy gets green light

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Treating cancer with "green" light

"We're developing a new therapy for cancer treatment. We injected a mouse with a non-toxic chemotherapy drug that you make toxic by illuminating the tumor. When you turn off the light, that's it," explains Professor Yoram Salomon, Biological Regulation Department, about the research he is conducting with Professor Avigdor Scherz, Plant Sciences Department.

The drug he is referring to is a water soluble derivative of chlorophyll, which is the green pigment of plants. Chlorophyll is the light-harvesting molecule, the antenna of this planet that harvests solar energy, later transforming it into useable fuels. Scherz and Salomon are taking this molecule and utilizing it for a completely different purpose.

They are applying the chlorophyll to photodynamic therapy, or PDT, a cancer treatment already in common use. The essential element in understanding PDT is that it uses a combination of drugs and light. Simply stated, the drug is injected into the patient's or animal's bloodstream, or directly into the tumor. Then, by exposing only the tumor to light in a controlled manner, the drug is activated and becomes toxic to cancer. Result: The drug-and-light combination destroys tumor cells while having little effect on healthy tissues.

However, states Salomon, "For the drugs used today, there are limitations." That's why their work is so important. PDT as it is currently practiced in a clinical setting is effective only against relatively flat and thin tumors, such as certain types of skin and bladder cancers. The new tandem approach promises to destroy tumors, the bulky, solid tumors that until now have been impenetrable by light.

Another limitation for patients undergoing standard PDT is that they must avoid sunlight for weeks following treatment because their skin becomes overly sensitive to strong light. In contrast, the "green" materials, which are modified to make them soluble in water, clear faster from the body. That may allow patients to tolerate outdoor light within a few days after treatment with less concern that the photosensitive materials will harm their skin.

"If successful, in the future our 'green' PDT could be a powerful new tool in the struggle against cancer," says Scherz. "The great advantage of this treatment over conventional chemotherapy is that the drug's action is confined to the illuminated tumor site, so that the damage to healthy tissues is minimized and side effects are significantly reduced," reports Salomon.

The materials were shown to kill cancer cells in tissue culture and they have successfully eradicated relatively large malignant melanoma tumors in mice. In tissue culture, they have destroyed other cancer cell types, including breast and colon.
 

More Good News

The scientists are also exploring the potential use of the new materials as antimicrobial drugs. This application of the chlorophyll derivatives may be particularly important in view of the growing problem of bacterial resistance to antibiotics. A recent study showing that chlorophyll derivatives effectively kill disease-causing bacteria was published in the December 1997 issue of Photochemistry and Photobiology, the journal of the American Society for Photobiology.


The development of "green" PDT for clinical use is being funded and will be clinically tested in a year or so by the Dutch company Steba Beheer NV, which has been granted a worldwide license for the product by Yeda Research and Development Co. Ltd., the Weizmann Institute's technology transfer arm.
Life Sciences
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The Picture Of Health

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3TP images of breast tumors


When a tumor is discovered, the first question asked is: malignant or benign? The usual method for making a determination is to do a biopsy. This can be painful and even disfiguring. And even when the news is good, it's a tough way to find out. All this may soon change.

A non-invasive alternative for discovering and distinguishing between tumors using magnetic resonance imaging (MRI) has been developed by the Weizmann Institute's Prof. Hadassa Degani, who is now successfully applying it to breast cancer in humans.

The technique, featured recently on the cover of Nature Medicine, can reveal tumors as small as one cubic millimeter, denote their nature and even indicate how aggressive a malignant tumor may be. Degani's method promises to allow doctors to make more accurate diagnoses and monitor and adjust therapies accordingly.

According to Degani, a member of the Biological Regulation Department, "Most breast tumors detected by mammography are revealed to be benign on biopsy, so a non-invasive method like MRI could help reduce the rate of unnecessary procedures."

With Degani's technique, patients are spared potentially harmful X-ray radiation or surgery. A dye-like contrast substance is injected into the bloodstream and is tracked as it moves into and out of the tumor and its surrounding tissue. The MRI image is built up using a technique Degani developed called 3TP (Three Time Point). In 3TP, a "snapshot" of the breast is made once before the dye is injected and twice more at intervals of several minutes. Recording each image takes from two to four minutes, instead of the usual several seconds. Unlike earlier attempts at MRI imaging of tumors, Degani's method provides high-resolution pictures on a computer screen, with benign and malignant tumors showing up in different colors.

In developing her revolutionary new method, Degani exploited the different properties of malignant and benign growths. In malignant tumors, the cells are densely packed with very little intercellular space between them, and they are fed by many small blood vessels that are porous and leaky. Benign tumors, on the other hand, are less densely packed and have fewer blood vessels.

After the dyes are absorbed, the cells reveal these physiological differences in color: red in areas of minimal leakage, green in areas with steady levels, and blue where the leakage is rapid. A benign tumor, having more space between cells and containing fewer blood vessels, takes up and releases the contrast substance slowly. In the denser malignant tissue, the dye passes through the tissue quickly and does not accumulate. The malignancy's many blood vessels are also more porous, leaking the color into the intercellular space. These traits make the 3TP images clearly definable as benign or cancerous tumors, and give new meaning to the phrase in living color.

Degani's team looked at 18 cases, eight of them fibroadenomas (benign tumors) and 10 of them breast cancers. The fibroadenomas looked mostly red with patches of green. In the cancerous tumors, blue predominated. Furthermore, the colors in the benign tumors were uniform and well-defined, denoting slow uptake, accumulation and wash-out. The malignant tumors showed colors distributed in chaotic, uneven patches, indicating wild and rapid processing.

The next step is large-scale clinical trials. If the results are consistent with the early findings, Degani's 3TP approach may become the tool of choice for detection and diagnosis of cancer in the breast and other organs.

This project was funded in part by the U.S. National Cancer Institute and the National Institutes of Health; the Israel Academy of Sciences and Humanities; the German-Israeli Foundation for Scientific Research and Development; and the Weizmann Institutes Canadian Women for Science.
Life Sciences
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Tumor Dependence on Blood Vessels Traced

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The dependence of tumor growth on the development of new blood vessels was, for the first time, traced in vivo through a noninvasive procedure developed at the Institute and described in a recent issue of Cancer Research.

A major concept in solid tumor physiology states that tumors can grow only to a size of approximately 1 mm in the absence of new blood vessels, due to limited nutrient and oxygen supply. While supporting evidence for this hypothesis has been accumulating, the new study -- carried out by doctoral student Rinat Abramovitch, technician Gila Meir and Dr. Michal Neeman of the Institute's Department of Hormone Research -- furnishes quantitative documentation of this phenomenon.

Making use of noninvasive magnetic resonance imaging (MRI), the Weizmann team found a consistent four-day lag in the growth of tumors implanted in immune-deficient mice. During this period, blood vessels near the tumor began to develop. Rapid tumor growth was observed only after the fourth day following implantation, which was also when the new blood vessels reached the tumor.

"The ability to observe the early stages of new blood-vessel development in vivo in a tumor with well-defined initial conditions will open new possibilities for the evaluation of the role of metabolic stress in this critical stage of tumor establishment," the scientists write.

This study also demonstrated that tumor-induced generation of vessels could be measured separately from vessel formation triggered by wound healing. The separate measurements were made possible by positioning the tumor 1 cm away from the site of incision and simultaneously monitoring both tumor expansion and the wound-healing process.

Nearly all solid tumors evolved through two phases -- avascular (without vessels) and vascular. Cells of avascular tumors usually do not invade or violate the integrity of their host. In contrast, vascularized tumors appear to compress, invade and destroy neighboring tissue. This critical point of tumor vascularization may thus become a favorable target for various therapies.

Dr. Neeman is the incumbent of the Dr. Phil Gold Career Development Chair of Cancer Research.
Life Sciences
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Operation of Major Breast Cancer Drug Explained

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Prof. Degani and Furman-Haran imaged tumor with MRI

One of the most puzzling aspects of the widely used breast cancer drug tamoxifen -- which shrinks estrogen-sensitive tumors yet is unable to kill cells from these tumors in tissue culture -- has been clarified by Weizmann Institute scientists working with doctors at the Sheba Medical Center near Tel Aviv.


The investigators found that tamoxifen destroys tumors by preventing them from maintaining their blood-capillary network. Without an adequately functioning life-support network, cancer cells die and the tumor regresses in size.

Participating in this study were group leader Prof. Hadassa Degani and graduate student Edna Furman-Haran of the Weizmann Institute's Department of Chemical Physics, Dr. Ada Horowitz and Iris Goldberg of the Department of Pathology of the Sheba Medical Center, and Dr. Antonio F. Maretzek, a visiting scientist from the University of Bremen.

Interest in tamoxifen stems from its wide use to prevent the recurrence of breast cancer in women who have undergone surgery to remove an estrogen-sensitive tumor. It is also being tested in patients in the United States and United Kingdom as an anticancer prophylactic in high-risk women.

Because only about half of breast tumors are estrogen dependent and potentially responsive to tamoxifen, the new Weizmann-Sheba study suggests seeking other drugs that destabilize the tumor capillary support system, and perhaps using them to control estrogen-independent breast tumors. Such new approaches could also complement tamoxifen therapy itself, as long-term treatment with the drug often leads to the appearance of estrogen-independent growths.

Using advanced magnetic resonance imaging (MRI) at high spatial resolution coupled with immunohistochemical techniques, Weizmann Institute and Sheba Medical Center researchers have studied how tamoxifen affects the growth of human breast carcinomas implanted in laboratory mice. They found that shortly after initiation of tamoxifen treatment, the tumors stopped growing and after two weeks, they showed an average 26% reduction in size and significant increase in the extent of necrosis. Specific histological staining of the endothelial cells comprising the microcapillaries showed a two-fold decrease in their density, indicating a reduced capacity of this tissue to deliver oxygen and vital nutrients.

This study was partially supported by the U.S.-Israel Binational Science Foundation and by the Israel Academy of Sciences and Humanities.
Life Sciences
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Anticancer Potential of Opiates Explored in Joint Study

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Dr. Jacob Barg and Prof. Zvi Vogel. Opiate receptors

 
A new study on the effect of opiates on cell reproduction may facilitate eventual use of such drugs in the treatment of cancer. This research -- carried out by Prof. Zvi Vogel and Dr. Jacob Barg of the Weizmann Institute's Department of Neurobiology along with Prof. Carmine Coscia of the St. Louis University School of Medicine -- was inspired by recent scientific papers documenting the inhibitory effects of opiates on DNA production in the fetal brain, as well as intestinal, lung and breast cancer cells.

In this study, parts of which were recently published in the Journal of Neurochemistry, the rate of DNA synthesis in fetal rat brain cells was measured. The researchers used aggregates of nerve cells and glial brain tissue supporting cells in order to mimic as closely as possible the situation in the developing brain.

The researchers found that of the three known types of opiate receptors in brain cells -- mu, kappa and delta -- only the first two are associated with inhibition of DNA synthesis, while the third is inactive. In addition, they demonstrated that opiates impede a key step in the transmission of intercellular messages ? phosphoinositol signal transduction -- which is also known to be linked to DNA synthesis. It is likely, therefore, that the capacity to impede phosphoinositol signal transduction is what enables opiates to inhibit DNA synthesis during brain development.

It is hoped that this fresh information may contribute to the development of new opiates capable of selectively slowing DNA synthesis in malignant cells with opiate receptors, thereby repressing the spread of certain tumors while leaving normal cells unharmed. "The side effects of opiates," says Dr. Barg, "are generally less severe than those of standard cancer therapies. A cancer victim would derive double benefit from these substances if they could be made to not only kill pain, but also to impede the spread of tumors."

Prof. Vogel holds the Ruth and Leonard Simon Professorial Chair.
 
Life Sciences
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