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Old 03-09-2011, 09:02 PM
gdpawel gdpawel is offline
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Default Researchers Show How Leukemia Develops After Cancer Treatment

Certain Chemotherapy Drugs Damage DNA

A team of 20 scientists from the US, England, and France has learned how certain chemotherapy drugs can lead to a particular type of leukemia several years after cancer treatment. The leukemia, called acute promyelocytic leukemia, represents about one-fifth of all leukemias that develop after chemotherapy.

About 1% of cancer survivors treated with chemotherapy will suffer one of its most devastating side effects, acute leukemia. The leukemia usually develops 2-7 years after treatment. Certain types of chemotherapy drugs, including some of those used to treat breast cancer and childhood cancers, are more likely to cause this side effect. Learning how the drugs cause the leukemia may lead to a better understanding of how to prevent it.

Like most cancers, leukemia develops because there is an abnormality in the cell's chromosomes, the tiny rod-like structures that contain DNA. DNA is the genetic material that controls all cell processes. Although chromosome abnormalities are found in many types of leukemia, promyelocytic leukemia has a very specific type, called a translocation. In a translocation, part of one chromosome breaks in two and attaches itself to a different chromosome that has also broken. The new chromosomes may begin to make a new protein at the site of the translocation that will cause the cell grow out of control. Promyelocytic leukemia always has a translocation between chromosomes 15 and 17 that seems to cause the leukemia.

The researchers studied DNA from the leukemia cells of 5 patients, of whom 4 had been treated for breast cancer. All had developed promyelocytic leukemia after receiving chemotherapy with either mitoxantrone or doxorubicin. The scientists looked for the break points in DNA from leukemia cells and tried to cause the same break points in normal DNA using the chemotherapy drugs.

The scientists were able to cause the same breaks in the normal cells by bathing them in one of the drugs and a naturally occurring (and necessary) enzyme called topoisomerase II. Topoisomerase II cuts the DNA so it can unwind and function. Normally, these breaks repair themselves. But the chemotherapy drugs seemed to make the topoisomerase II enzyme work at a super high speed and make many more breaks than could be repaired.

We now know how these particular chemotherapy drugs can lead to leukemia in a small number of people. This study also provides clues about how leukemia develops in people who haven't received any drugs. In the future those clues may lead to new approaches in preventing this disease. The study will also help future investigators learn how other chemotherapy drugs lead to other forms of acute leukemia.

Citation: "DNA topoisomerase II in therapy-related acute promyelocytic leukemia." Published in the New England Journal of Medicine (Vol. 352, No. 15: 1529-1538). First author: Anita Mistry, PhD, Guy's, King's and St. Thomas' School of Medicine, London.
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Old 03-09-2011, 09:08 PM
gdpawel gdpawel is offline
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Default Can chemotherapy ever be bad, in cases where it apparently works?

Life has been shortened by chemotherapy. The most likely mechanisms for this life shortening are toxicities of the drugs on the patient's body, such as immunosuppression and organ damage, and the mutagenic effects (changes in form) of chemotherapy on the genetically-unstable tumor, driving the tumor into a state of more aggressive behavior.

You might kill off a whole lot of cancer, only to cause a mutation in the remaining cancer, such that the remaining cancer behaves in a more agressive fashion. Like when chemotherapy on an ER+ cancer brings about a remission, but in the process also causes any remaining cancer to become ER-.

It seems entirely reasonable that effective, although mutagenic therapy would be preferred over ineffective, mutagenic therapy. Chemotherapy not only causes mutations, which might make a given cancer more agressive, but it causes second malignancies as well (example: you cure testicular cancer, only to cause leukemia).

Chemotherapy has many adverse effects which can affect any system of the body. Some may not appear until after treatment is completed. Some adverse effects include hypersensitivity reactions, ocular, cardiac, pulmonary, hepatic, renal, neurological and vascular toxicities.

A major obstacle in controlling cancer growth and metastasis in patients is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice. The norm is to use chemotherapy that is randomized or standardized in relation to the target organs or tumor origins.

Because tumors originate from a wide variety of genetic backgrounds, most cancer cases have become unsuited to the use of such standardized chemotherapy. Since no single drug or combination has been found to be optimal for cancers of all origins, developing a good and clinically practical drug selection system is no less important than the discovery of new drugs.

All laboratory tools should be at the disposal of the oncologist, for the patient. Chemosenstivity testing doesn't change cancer biology, it only helps reveal biology. It lowers the probability that certain drugs will work. It raises the probability that others will work. It doesn't say anything at all about whether the drug(s) will increase the aggressiveness of the tumor or cause a second malignancy.

When your first-line treatment does not work, there are several downsides:

It can take months for tests to confirm whether chemotherapy has been effective. If it has not, the cancer may have progressed. And then the patient, if strong enough, has to go back to square one and try again with something new.

Ineffective chemotherapy can cause the patient to become sicker or suffer serious side effects with no treatment benefit.

Many chemotherapies can cause mutations leading to drug-resistant tumors. Exposure to drugs may actually diminish subsequent benefit from treatment.

With patients absorbing a larger percentage of their own costs of care, the expenses associated with ineffective treatments become a personal financial burden.

Ineffective chemotherapy can diminish not just the quality of life but also the quantity of life through organ toxicity, immunosuppression, and/or by inducing mutations in genetically unstable tumor cells to more aggressive phenotypes.

The tumor microenvironment is characterized by regions of fluctuating hypoxia, low pH, and nutrient deprivation. Each of these microenvironment factors has been shown to cause severe disturbance in cell metabolism and physiology.

Both in vivo and in vitro data demonstrate that exposure of tumor cells to adverse conditions can directly cause mutations, contributing to genetic instability (Mutat Res;1998 May 25;400[1-2]:439-46).

Mutagenesis induced by the tumor microenvironment

[url]http://www.ncbi.nlm.nih.gov/pubmed/9685702

Genetic Instability Induced by the Tumor Microenvironment

[url]http://cancerres.aacrjournals.org/content/56/24/5754.full.pdf

Genetic instability and the tumor microenvironment

[url]http://www.ncbi.nlm.nih.gov/pubmed/15603753
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Last edited by gdpawel : 03-03-2013 at 01:23 PM. Reason: corrected url address
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Old 03-22-2011, 09:27 PM
gdpawel gdpawel is offline
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Default New Cancer Therapies Unseat Traditional Chemotherapy Regimens

Special Report: Can New Therapies Unseat Traditional Chemotherapy Regimens in Acute Myelogenous Leukemia?"

With optimal standard chemotherapy, 70% of acute myelogenous leukemia (AML) patients enter remission; however, only 20% live to become long-term survivors, and the average time of AML-patient survival is merely 18 months. Despite the development and success of newer cancer therapies (such as monoclonal antibodies [MAbs]) for the treatment of other cancers, therapies to treat AML have varied little over the past few decades. Although the AML pipeline is rich with new agents (44 confirmed agents in Phase I-III development), these drugs face a steep uphill battle in proving they are at least as safe and efficacious as the numerous, less expensive chemotherapeutic agents that currently dominate the AML market.

Questions Answered in This Report

- An AML diagnosis is not always easy to determine initially because AML's symptoms can appear to be caused by other ailments. How is the diagnosis of AML ultimately made? What kinds of diagnostic tests are used, and what biological markers are indicative of an AML diagnosis?

- Treatment of AML has changed very little in the past 30 years, with less expensive, generically available chemotherapies dominating the market. Why have no other agents challenged the commanding hold that chemotherapy has on the AML market? Is this positioning likely to change in the near term? What agents are in the clinical pipeline?

- Elderly AML patients (aged 60 or older) face an even grimmer prognosis than their younger counterparts. What are the reasons for this poor prognosis? Is this poor prognosis a result of biological factors in this population? Is it compounded by comorbid conditions that occur primarily in the elderly?

- Acute promyelocytic leukemia (APL), a subset of AML, is remarkably curable, in stark contrast to the other subsets of AML. How does APL differ from AML? Why is APL easier to cure than AML?

Source: MarketResearch.com

[url]http://www.marketresearch.com/product/display.asp?productid=2663746&xs=r[/url]
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