Cell Profiling may offer better mesothelioma treatments

[gpawelski]

A California based cancer physician is offering a new test that could tell which cancer drugs will be most effective on an individual patient’s cancer. This approach could lead to improved treatment of mesothelioma in the future.

Dr. Larry Weisenthal's new series of tests, called Functional Tumor Cell Profiling (FTCP), is a process that takes live cancer cells from a patient and exposes them to a series of anti-cancer drugs to see which will work and which won’t. FTCP could save patients and doctors time and money, while avoiding painful and ineffective treatments.

FTCP incubates cancer cells (a gram being the recommended amount) over a 96 hour period. During this time, the sample is exposed to more than twenty different anti-cancer drugs, and in some cases, combinations of drugs. After each drug is used on the sample in multiple doses (to ensure accuracy), three different methods are used to measure the effectiveness of the drug. The results are then compared to the Weisenthal Cancer Group index database. Using this information, Dr. Weisenthal rules out which cancer treatments won’t work, and recommends which show promise.

Weisenthal, evaluates all the samples himself, spending 6-8 hours on each one. For Dr. Weisenthal and his team to use FTCP, they must receive a live cancer specimen, preferably a solid mass, although malignant effusions are often useable as well. The cost of the procedure is around $5000. Medicare covers the process, as do most insurers.

Source: Mesothelioma Aid

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Scientists have long been perplexed by the ability of cancerous tumors to regenerate so quickly after chemotherapy. This is one reason mesothelioma is such a tough disease. New research with mice subjects indicate that the body’s own defense mechanisms help the tumors rebound. The University of Toronto researches who conducted the study also believe their work points to a new set of drugs that could minimize this unwanted side effect of chemotherapy.

"Chemotherapy remains the most commonly employed form of systemic cancer treatment. However, although partial or complete shrinkage of tumor mass is frequently induced in chemotherapy-responsive tumors, survival benefits of such responses can be compromised by rapid regrowth of the drug-treated tumors," says senior study author Dr. Robert S. Kerbel of the Sunnybrook Health Sciences Centre in Toronto.

Kerbel and his team found that many chemotherapeutic treatments not only attack the cancer in a patient, but the blood vessels around the site that supply the tissue with nutrients and oxygen. In theory this would be beneficial—as a way to cut off the cancer’s supply lines—but in reality the body reacts in a way that actually makes sure the tumor receives more of the body’s resources after chemotherapy is over.

As a defense mechanism, the body directs “circulating endothelial progenitor" (CEP) cells to the damaged blood vessels around the tumor. CEP cells are blood vessel precursors, and they repopulate the area and enable the tumor to receive the blood and oxygen it needs to regrow.

The process of sending CEP cells to the site begins with a cellular growth factor called SDF-1alpha. Anti-angiogenic drugs that block the formation of blood vessels or a compound that specifically targeted SDF-1alpha, used in concert with chemotherapy, could reduce the chances of cancer regrowth.

"We view this as a yin-yang, action-reaction situation," Kerbel said. "The primary action is the effect of the drug on the tumor. The reaction is the host response, which compromises part of the action, and you want to blunt that with an antiangiogenic drug and/or something targeting this [protein] SDF-1. That's what this paper is all about."

The new research could help explain why some antiangiogenic drugs work well with chemotherapy, while others do not. "Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy," explained co- author Dr. Yuval Shaked.

The new research helps scientists understand the process that the antiangiogenic drugs are trying to correct, thereby helping to explain why some combinations of chemotherapy and antiangiogenic drugs are more effective than others.

“Our findings provide a potential explanation of why not all chemotherapy drugs will necessarily have their efficacy enhanced by the addition of an antiangiogenic agent when the mechanism involves blunting CEP mobilization acutely induced by the chemotherapy drug," Kerbel said.

The research appeared in the Sept. 9, 2008 edition of the Journal Cancer Cell.

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A study published in the European Respiratory Journal last April, revealed that talc stimulates healthy cells to produce endostatin, a hormone considered the magic bullet for treating metastatic lung cancer. The University of Florida researchers say talc is an exciting new therapeutic agent for cancers largely considered incurable.

They found that talc causes tumor growth to slow down and actually decreases the tumor bulk. Talc is able to prevent the formation of blood vessels, thereby killing the tumor and choking off its growth. The tumors appeared to grow much slower and in some cases completely disappeared.

Scientists have only recently discovered that talcum powder stunts tumor growth, though the mineral has been used for almost 70 years to treat the respiratory problems that accompany metastatic lung cancer. About half of all patients accumulate fluid around the surface of the lungs, a condition known as malignant pleural effusion. That fluid can press down upon the lung, impair the breathing of the patient and cause the patient to feel very short of breath.

Pleural effusions indicate that the cancer, which might have started in the breast, lung or gastrointestinal tract, has spread throughout the body. The prognosis for the roughly 200,000 patients afflicted with this condition is poor: Many die within six months.

To make life more bearable for these patients, doctors close the extra space between the lung and the chest wall, where the troublesome fluid collects. The trick is gluing the two surfaces together. Talc is blown into the patients' chest cavity to irritate the tissue and create tiny abrasions. When the lung tissue heals, it becomes permanently adhered to the chest wall without impairing the patients' breathing. The effects of the procedure, called medical thoracoscopy with talc pleurodesis, are immediate and last a lifetime.

The Food and Drug Administration approved talc for use in medical thoracoscopy in 2003. Doctors have noticed that patients who undergo medical thoracoscopy with talcum powder live up to 18 months longer than expected.

Talc has added benefits besides causing scarring and taking away the fluid that surrounds the lung. The cells that cover the lining of the lung are stimulated by the presence of talc to produce a factor that inhibits the growth of blood vessels and kills the tumor cells themselves.

Less than one day after treatment with talc, patients began producing 10-fold higher levels of endostatin, a hormone released by healthy lung cells. Endostatin prevents new blood vessels from forming, slows cell growth and movement, and even induces nearby tumor cells to commit suicide. All of these make it hard for tumors to grow and spread into healthy lung tissue.

What is being done is the normal pleural mesothelial cells continue to produce endostatin. Talc doesn't go away. Talc stays in the chest cavity, constantly causing the normal cells to produce this factor that inhibits the growth of the tumor. And the antitumor effects of talc appear to be long-lasting.

This work will undoubtedly have a significant influence on future clinical trials dealing with the treatment of pleural malignancies, including lung cancer, mesothelioma and metastatic adenocarcinoma involving the pleural surfaces.

Source: University of Florida

http://www.ufscc.ufl.edu:80/Patient/con ... e&id=39928

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Talc inhibits "adherence independent growth" of tumors in vitro and in vivo

Talc Induces Apoptosis in Human Malignant Mesothelioma Cells In Vitro

Am. J. Respir. Crit. Care Med., Volume 161, Number 2, February 2000, 595-600

NAJMUNNISA NASREEN, KAMAL A. MOHAMMED, PATRICK A. DOWLING, MELISSA J. WARD, GABRIELLA GALFFY, and VEENA B. ANTONY

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Veterans' Affairs Medical Center, Indiana University School of Medicine, Indianapolis, Indiana

Pleurodesis with talc is an accepted method for the treatment of symptomatic pleural effusions secondary to mesotheliomas. Patients with mesothelioma who have talc-induced pleurodesis have a lower morbidity than do those who do not have pleurodesis. The mechanisms whereby talc mediated these effects were considered to be secondary to a decrease or absence of a pleural effusion. The possibility that talc may directly affect malignant cells was not considered. The present study was designed to evaluate if talc directly effects cell death of malignant mesothelioma cells (MMC) or normal pleural mesothelial cells (PMC). Three confluent MMC and PMC were exposed to talc for 24, 48, and 72 h. In parallel experiments, glass beads similar in size to talc were included as control. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) and DNA electrophoresis. Our results demonstrated that talc at a therapeutically achievable concentration (6 µg/cm2) induces significant apoptosis in MMC. Talc-induced maximum apoptosis in MMC (39.50 ± 2.55%, 31.87 ± 4.69%, and 15.10 ± 3.93% in CRL-2081, CRL-5820, and CRL-5915, respectively) at 48 h, which was significantly (p < 0.05) greater than that in control cells. Electrophoresis of DNA isolated from talc-exposed MMC demonstrated the typical ladder pattern of internucleosomal DNA cleavage. Talc did not induce apoptosis in PMC, and glass beads did not cause significant apoptosis in either MMC or PMC. The present study has demonstrated that talc induces apoptosis in MMC without affecting normal mesothelial cells of the pleura. Nasreen N, Mohammed KA, Dowling PA, Ward MJ, Galffy G, Antony VB. Talc induces apoptosis in human malignant mesothelioma cells in vitro.