Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor. This type of medicine is used in treatment of leukemia (specifically chronic myeloid leukemia.) Nilotinib is considered a “second-generation” Bcr/Abl tyrosine kinase inhibitor, building on the success of imatinib. Because many patients develop resistance to imatinib, there is excitement about nilotinib.

Nilotinib is an analog of imatinib with similar multiple kinase targets, but without inhibition of the Src gene. (This gene regulates tyrosine kinase proteins that in turn affect whether cells multiply or die.) Tyrosine kinase inhibitors interfere with cell communication and growth. They have been of great interest to scientists in recent years who hope to use them as an option to treat cancer.

Nilotinib is used for leukemia, There was interest in using it to treat gastrointestinal stromal tumors and formal clinical trials were conducted in this area, but the nilitonib did not prove effective. While nilotinib may replace imatinib in leukemia treatment, imatininib is still preferred in GIST therapy.

The “binding mode” of nilotinib is energetically more favorable than that of imatinib. This results in a more selective targeting of the malignancy. Nilotinib has been shown to have an approximately 20-fold increased potency in kinase and proliferation assays compared to imatinib. This is especially important for older patients and they tend to have trouble tolerating imatinib treatment. The higher dosages required for imatinib make it tough; nilotinib is hoped to alleviate the side effects but still be effective.

Researchers have been interested in aurora kinases as targets for cancer therapy and seveal drugs are in development. Oncogenic BCR-ABL tyrosine kinase, which is deregulated in as many as 95% of chronic myeloid leukemia (CML) patients and in ~20% of adult Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients. ABL kinase domain mutations have been implicated in the resistance to imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients.

Mast cells in tumors are affected by the new class of anti-cancer agents called kinase inhibitors, which includes nilotinib. Inside the body, mast cells regulate t-cells, promote blood clots, and enable the growth of blood vessels. The kinase inhibitors are considered a form or “targeted cancer therapy” because they are selective in the type of cells they affect.

Potential Alzheimer’s Treatment?

Researchers are looking at nilotinib as a treatment for Alzheimer’s disease. Long thought to be caused by amyloid-beta plaques in the brain, some scientists are speculating that a protein called tau And a nilotinib is thought to be a potential way to lower tau levels. If the tau triggers the death of brain cells and nilotinib, a kinase inhibitor, can clear malfunctioning tau from tiny crevices in the brain, we will not only have learned something about this form of dementia, but we will have a valuable treatment. Research continues.

Chemists created nilotinib with the idea of improving the target specificity of an earlier kinase inhibitor, imatinib. Studies show it is 20 to 50 times stronger than imatinib. Nilotinib is also intended to be specific for BCR-ABL. It therefore has a lower impact on the liver.

The manufacturer, Novartis, says Nilotinib caused a hematologic response in 74% of cases in clinical trials for use on Ph+ CML leukemia. CML makes up 15% of leukemia cases in adults, and the Philadelphia chromosome (the Ph+ designation) is present in most CML patients.

This agent also inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs).

The dosage of nilotinib directly affects the patients’ T-cell count in the blood. A German study found that the dose needed to be higher than the normal clinical dose to control cytokine production.

As scientists learn more about kinase inhibitors as a class of drug, it appears that these drugs seem to improve the action of cancer treatment in certain conditions, but actually have detrimental effects in other conditions. For clinical evaluation purposes, these conditions are going to most often be the presence of other chemotherapy agents.

In October 2007, the FDA approved Nilotinib for CML. Specifically, the medicine was approved for the chronic phase and accelerated phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia. Doctors have the authority to prescribe the medicine for other conditions, and it may happen that nilotinib is combined with other medicines for treatment. The approval process for nilotinib was faster than for most anti-cancer drugs, partly because of its similarity to imatinib.

In June 2008 Italian doctors presented evidence of the efficacy and tolerability of nilotinib in CLL. The complete cytogenic response among patients in their tests was 84%.

Treatment with Nilotinib

Nilotinib is taken orally. Unlike some chemotherapy agents, it is not given by IV drip. It is “bioavailable” if swallowed. The manufacturer makes capsules with 200 mg of the active drug; the rest is filler.

Like any medicine, especially any chemotherapy agent, it is important to discuss nilotinib with your doctor before taking. Your doctor probably will not let you take it if you are pregnant or might become pregnant. Nilotinib potentially interferes with a wide range of antibiotics. You need to be careful of other chemotherapy drugs, too. This is why chemotherapy should only be administered under supervision of highly trained medical oncologists.

Nilotinib is effective over all phases of leukemia, and different subtypes of leukemia. That’s one reason it has found acceptance as second-line treatment for CML.

Researchers found Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs.

A write-up of targeted therapy for leukamia speculated the future CML treatments could employ combination regimens two or more agents. It has been suggested that use with the kinase inhibiotor imatinib could help increase the intracellular concentration of nilotinib and lead to better efficiacy.

The aminopyrimidine inhibitor AMN107 (Nilotinib) was rationally designed to antagonize the aberrant tyrosine kinase activity of Bcr-Abl-positive cells.

Lung Treatment?

There is also concern that nilotinib causes interstitial lung disease. But there has been work in use of nilotinib (and tyrosine kinase inhibitors more generally) to treat people with acute lung injury.

Nilotinib is better tolerated than most anti-cancer drugs. It has side effects, but all drugs have potential side effects in some people. It is particularly recognized for not suppressing red blood cell production the way many chemotherapy drugs do. Nilotinib is well tolerated even over long periods of use.

Nilotinib may cause QTc prolongation (an irregular heart rhythm that can lead to fainting, loss of consciousness, seizures, or sudden death). This information comes from the federal government’s MedlinePlus website on Nilotinib.

About Leukemia

Chronic myelocytic leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl.

Leukemia, a form of cancer, strikes at the patient’s bone marrow. The disease’s name literally means “white blood,” and is derived from the fact that in most cases, Leukemia negatively affects the person’s blood cells. Leukemia causes the bone marrow to create an excessive amount of immature white cells (or blasts) with an irregular shape. As a result of their irregular shape, the white cells are not able to carry out their intended functions. Eventually these white blood cells begin the crowd in the marrow, and interfere with the production of the various other blood-cell types. This leads to swelling and pain.

Denying the Symptoms

Part of the problem with Leukemia, as with most any cancer, is that people are often not diagnosed early enough. This is largely because when they experience the symptoms, they try to rationalize them away. So what are the symptoms that should send a warning signal to people to go to the doctor? There are many, but the main ones are:

• Regular unexplained tiredness and fatigue
• Malaise – that undefined slight feeling of bodily discomfort
• Unexplained bleeding
• An unusual amount of bruising from just the slightest hits.
• Excessive weakness
• Unexplained drastic weight loss
• Pain in the joints and other bones
• Unexplained fever and infection
• Regular sense of “fullness,” even when it’s been a while since you’ve eaten
• Unusual pain in the abdomen
• Unexplained enlarging of the liver, spleen or lymph nodes

While many of these symptoms apply to several conditions, some minor, if you experience a few of these, you should consult a physician. Or if you’ve noticed these symptoms in a friend or loved one, gently encourage them to see a doctor. A high percentage of people survive Leukemia if it’s caught early enough. In fact, in the past half century, the survival rate has more than tripled, precisely because more people pay attention to the symptoms. But early detection is key.

Causes of Leukemia

Nobody knows exactly what causes Leukemia. It has been documented that persons exposed to high levels of benzene at work or to high amounts of irradiation get Leukemia more often than the regular population, but nobody has yet been able to explain why. There has also been some evidence that exposure to formaldehyde can be a risk factor, but again, there’s not explanation why this is.

Diagnosis and Treatment of Leukemia

Once the symptoms have motivated you to seek a doctor’s opinion, there are several ways that he might attempt to diagnose whether or not you or the patient has Leukemia. At first, he will order blood tests. Things that will indicate to him the presence of Leukemia will be Anemia (a red-blood-cell count that is too low, Leukopenia (a low count on the white cells), Neutropenia (a low number of neutrophils, white cells that destroy bacteria), Thrombocytopenia (too few blood-clotting platelets), or Thrombocytosis (too many platelets). If these tests indicate the possibility of Leukemia, more in-depth tests will be conducted, which could include any of the following:

• Bone marrow tests: A sample of the one marrow is taken from the pelvis as the patient through an injection with a needle that sucks out the sample.
• Lymph Node Biopsy: The patient is asleep as a doctor removes the lymph node for diagnosis.
• Lumbar puncture: The attending doctor inserts a small needle in the lower back’s spinal cavity to withdraw spinal fluid, which will then be examined for Leukemia cells.

Once a positive diagnosis has been made, there are several ways to treat the Leukemia. Which type works best in any situation depends on the patient’s age, health, and how far the cancerous cells have spread. And in some cases, multiple forms of treatment might be used. The accepted treatment options are:

• Chemotherapy: This is the process of killing the cancer cells with special chemical agents, which can be taken through a pill or be injected into a vein.
• Immunotherapy: This is a treatment option that bolsters the patient’s immunity through the use of certain substances.
• Kinase inhibitors: Imatinib mesylate, dasatinib and nilotinib are three drugs that inhibit proteins that make Leukemia deadly.
• Radiation therapy: This is the treatment method that uses X-Rays to stop Leukemia cells from growing and ideally to kill them.
• Bone marrow transplant: As the name implies, this procedure removes the bone marrow with the Leukemia cells and replaces it with good marrow. The process is normally used in conjunction with either chemotherapy or radiation therapy.
• Stem cell transplant: Unlike a marrow transplant, cells are taken from stem cells in the person’s blood cell; these cells are then transplanted in place of the cells with Leukemia.