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Old 12-11-2009, 10:46 AM
Dross Dross is offline
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Default Anti-estrogens may offer protection against lung cancer mortality

SAN ANTONIO – Anti-estrogens as therapy for breast cancer may also reduce the risk of death from lung cancer, according to study results presented at the CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 9-13, 2009.

"We found a reduction in lung cancer mortality among women treated with anti-estrogens for breast cancer. This work builds on previous studies that had suggested estrogens have a role in lung cancer development and progression," said Elisabetta Rapiti, M.D., M.P.H., medical researcher with the Geneva Cancer Registry, University of Geneva, Switzerland.

Rapiti and colleagues evaluated whether anti-estrogen therapy for breast cancer patients reduced their risk of subsequently developing and/or dying from lung cancer.

The study included 6,715 women living in the Geneva canton of Switzerland who were diagnosed with breast cancer, between 1980 and 2003. Forty-six percent of the women received anti-estrogen therapy, primarily tamoxifen.

By the end of the study period, 40 cases of lung cancer developed. There was no difference in the incidence of lung cancer among women with or without anti-estrogens compared with the general population. However, the risk of dying from lung cancer was significantly lower among women who received anti-estrogen therapy.

"Our results are particularly relevant to the research agenda exploring endocrine treatment(s) for lung cancer," said Rapiti. "If prospective studies confirm our results and find that anti-estrogen agents improve lung cancer outcomes, this could have substantial implications for clinical practice."

Phase II clinical trials are currently underway in a number of centers to evaluate the use of anti-hormone therapy as an adjunct to traditional chemotherapy for lung cancer, according to Rapiti.

Last edited by gdpawel : 12-03-2011 at 12:06 AM. Reason: post full article
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Old 12-14-2009, 11:20 PM
gdpawel gdpawel is offline
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Default High-dose Tamoxifen (anti-estrogen) Therapy

Selection of the optimal chemotherapeutic agent is one of the major problems in oncology. Even with the advent of large multicenter therapeutic trials for the determination of chemotherapeutic efficacy, individual variability in tumor characteristics often leads to a poor therapeutic outcome.

A major cause of failure to many of the natural products used as chemotherapeutic agents is multiple drug resistance (MDR). The over expression of P-glycoprotein and other proteins involved in cellular transport is a frequent cause of MDR, although detoxification by biochemical means, DNA replication and repair, or other mechanisms may be involved.

A genetic predisposition which causes multiple proteins to dot the surface of tumor cells. These proteins are known as P-glycoprotein, or PGP. PGP is a transmembrane efflux pump- it pumps harmful things from the inside of the cell to the outside of the cell. In many cases, PGP is at least partially responsible for a patient's decreased sensitivity to taxane-based chemotherapy (taxol, taxotere, paclitaxel). As soon as the drugs enter the cancer cells, the PGP pumps start pumping the drugs out.

The presence of P-glycoprotein (PGP), signaled that the patients would not respond well to chemotherapy. PGP is primarily responsible for inducing multi-drug resistance, in which the tumors become resistant to many chemotherapy drugs after treatment with just one drug. PGP effectively pumps the drug out of tumor cells before it has time to kill the cells. PGP is just one protein implicated in multi-drug resistance. Harpole found that the 88 patients with PGP survived 20.9 months on average, while the 24 patients without PGP had an average survival of more than 5 years after diagnosis.

P-glycoprotein (PGP) is a plasma membrane protein which acts as a localized drug transport mechanism, actively exporting drugs out of the cell. The effects of PGP on the distribution, metabolism and excretion of drugs -- including protease inhibitors -- in the body is great. PGP activity decreases the intracellular concentration of cancer drugs, enabling resistance to develop to them.

The normal physiological function of PGP in the absence of therapeutics or toxins is unclear. Studies of MDR-1 knock-out mice (mice bred in the lab specifically for the absence of the MDR-1 gene and, therefore, no PGP activity) show that they have normal viability, fertility and a range of biochemical and immunological parameters.

Predictably, they do have delayed kinetics and clearance of vinblastine, and they accumulate high levels of certain drugs (vinblastine, ivermectin, cyclosporin A, dexamethasone and digoxin) in their brains. The mice also demonstrated marked increases in the levels of these drugs in the tests, ovaries and adrenal gland compared with wild-type mice. It has been reported that some MDR-1a knock-out mice develop a severe, spontaneous intestinal inflammation similar to human inflammatory bowel disease.

The majority of published data suggest that PGP acts as a transmembrane pump which removes drugs from the cell membrane and cytoplasm. It has further been proposed that PGP acts like a hydrophobic vacuum cleaner or "flippase," transporting drugs from the inner leaflet of the plasma membrane lipid bilayer to the outer leaflet or to the external medium.

There have been various attempts to classify compounds based on their effect on or interaction with PGP. A number of chemicals, including anticancer drugs, have been categorized based on their effect on ATPase activity of human PGP.

Class I compounds in low concentrations stimulate ATPase activity and in high concentrations inhibit it. Kinetic analyses show they have high affinity for the active site and low affinity for the inhibitory site. They include vinblastine, verapamil and taxol.

Class II compounds stimulate ATPase activity in a dose-dependent manner without any inhibition and interact only with the active site. They include bisantrene, valinomycin and diltiazem.

Class III compounds, which bind to the inhibitory site with high affinity, inhibit both basal and verapamil-stimulated ATPase activity. They include cyclosporin A, rapamycin and gramicidin D.

Some studies support a model of PGP in which there is a region or multiple regions of interaction rather than one or two simple binding sites. Molecules interacting with PGP may be classified as "substrate" or "antagonist."

It has also been demonstrated that one possible mechanism of action for PGP-mediated resistance to chemotherapeutic agents is through gene rearrangement.

The reasons for the association between treatment of breast cancer with a taxane-containing chemotherapy regimen and an increased incidence of CNS involvement could be that taxanes are very lipophilic, their concentration in the CNS is very low after their intravenous administration. Taxanes are unable to penetrate the intact blood-brain barrier, the concentration of radiolabeled paclitaxel in the cerebrospinal fluid is found to be significantly lower than in other organs, and thus undetectable in the brain, in the spinal cord or in any other site of the CNS. Also, paclitaxel is exported from the p-glycoprotein and other ATP-binding cassette transporters placed at the luminal membrane of brain capillaries, as an explanation for the low concentrations of taxanes in the CNS.

In conjunction with immunocy-tochemistry and molecular techniques, flow cytometry has been essential for measuring the expression of cell surface and intracellular markers of MDR, assessing the intracellular accumulation and efflux of chemotherapeutic drugs, and studying the other mechanisms leading to MDR.

The identification of intrinsic or acquired MDR is potentially of significant clinical value in planning chemotherapy. The reliable in vitro prediction of tumor cell sensitivity to antineoplastic agents prior to therapy in individual cancer patients has been a long-sought goal of oncologists. Flow cytometric measurements of cell viability or apoptosis have been used to design drug treatment protocols and improve accuracy and reliability.

For example, high-dose tamoxifen has been turning up, over the years, with very nice responses in cell culture assays. It turns up synergistic (cooperative) in brain tumors, lung cancers, ovarian cancers and the like. Navelbine is often potentiated by high-dose tamoxifen on in vitro testing. Tamoxifen at concentrations of 2.5 micromolar or greater significantly inhibits the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance).

In most patients, this level can be achieved starting the day before, the day of, and the day after chemotherapy. It is usuall well tolerated, though some patients have GI side effects, and some have headaches which often respond well to Imitrex or similar anti-migraine medications.

Selective Estrogen Receptor Modulators (SERMs) are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

In pharmacology the term agonist-antagonist is used to refer to a drug which exhibits some properties of an agonist (a substance that fully activates the neuronal receptor that it attaches to) and some properties of an antagonist (a substance that attaches to a receptor but does not activate it or if it displaces an agonist at that receptor it seemingly deactivates it thereby reversing the effect of the agonist).

A cell-based functional profiling assay conducted on human tumor samples utilizes native microspheroids (fresh, live cells, not cell lines) replete with vascular, stromal and inflammatory cells to analyze cellular responses in the context of the tumor microenvironment. This snapshot of cellular response recapitulates patient response to cytotoxic compounds, signal transduction inhibitors, and growth factor agonists/antagonists in real time.

SERM tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. Agonist (potentiating) effects at high doses. Sometimes agents can "chemosensitize" tumor cells. To alter susceptibility of a targeted cell or organism having become ineffective, becomes effective again. There is a chemosensitizing effect of tamoxifen.

Sources:
Cell Function Analysis
Treatment Action Group

The Human ATP-Binding Cassette (ABC) Transporter Superfamily [url]http://www.ncbi.nlm.nih.gov/books/NBK31/
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Old 01-12-2012, 11:13 PM
gdpawel gdpawel is offline
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Default Lung Cancer Prevention Potential For Estrogen-Targeting Drug Combo

A combination of drugs that target estrogen production significantly reduced the number of tobacco carcinogen-induced lung tumors in mice, according to results from a preclinical study.

"Antiestrogens have been shown to prevent breast cancer in some women," said Jill M. Siegfried, Ph.D., professor in the department of pharmacology and chemical biology at University of Pittsburgh Cancer Institute. "If antiestrogens can prevent lung cancer as well, this would be a major advance, because these drugs are safe to give for long periods and there are no approved ways to prevent lung cancer."

Siegfried presented the results at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine, held Jan. 8-11, 2012.

Most lung cancers are positive for a type of estrogen receptor that makes lung tumors grow when exposed to estrogen. In addition, an enzyme in the lung called aromatase produces estrogen. Siegfried and colleagues hoped that by blocking this estrogen receptor and the aromatase enzyme, they might be able to prevent estrogen-sensitive lung tumors.

To test this theory, they conducted a study on two groups of female mice: one group that was currently being exposed to a tobacco carcinogen and one that had past exposure to a tobacco carcinogen and in which some precancerous cells had already formed. The mice were assigned to treatment with a placebo, the aromatase inhibitor anastrozole, the antiestrogen fulvestrant or a combination of anastrozole and fulvestrant.

"The first model asks whether the treatments inhibit the process by which cancer is first started before it is even detectable under the microscope, and the second asks whether the treatments inhibit the process by which microscopic precancers develop into visible tumors," Siegfried said.

In the first model, the combination treatment given during carcinogen exposure resulted in significantly fewer lung cancer tumors compared with placebo or either treatment alone. The tobacco carcinogen was stopped once treatment began to maximize its ability to halt lung cancer development. Combination treatment also resulted in maximum antitumor effects in the second model, where precancerous cells were already present.

According to Siegfried, these results suggest that antiestrogen treatment combined with an aromatase inhibitor prevents lung cancer development during tobacco carcinogen exposure and after carcinogen damage to the airways has already occurred.

Siegfried said that ultimately, the hope is that this research could lead to an approved treatment that could greatly reduce the risk for an ex-smoker to develop lung cancer.

"We may be able to prevent lung cancer in people who have been previously exposed to tobacco carcinogens using some of the same antiestrogen drugs that can prevent breast cancer," Siegfried said. "A lot of work needs to be done to determine who would benefit from this therapy, and these drugs would need to be tested in clinical trials in those at high risk for lung cancer."

Source: American Association for Cancer Research
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