Bosutinib

Bosutinib is a third generation tyrosine kinase inhibitor. It is being tested in clinical trials and looks very promising. It has been useful in patients whose leukemia is resistant to both first and second generation tyrosine kinase inhibitors. It is a dual kinase inhibitor. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis (cell death). Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors. It seems to cause fewer side effects because it more selectively inhibits the faulty proteins in the leukemic cells and doesn’t affect similar proteins in normal cells as much as the earlier drugs do.

Bosutinib is also classified as a histone deacetylase (HDAC) inhibitor. A bunch of new drugs in this class have been developed. They induce differentiation and/or cell death in tumors.

Bosutinib is going through the phases of drug testing necessary to obtain United States FDA approval. In the first study, reported in 2007, 69 patients with either CML or ALL whose cancer was resistant to other drugs were treated with bosutinib, which is also known as SKI606. This study determined the best dose for the drug, which is 500 mg. a day. Bosutinib is given orally.

Phase II involved 98 patients with CML, many of whom had become resistant to either imatinib or nilatib and dasatinib. 23 patients resistant to imatinib had a complete response to bosutinib. Complete response is defined as a normal blood count. These 23 patients represented 74% of the imatinib-resistant patients. The researchers were able to evaluate more thoroughly a group of 36 patients to look at their Philadelphia chromosomes. Of the 36, 15 had a major response; 12 of the 15 had a complete response, meaning that they no longer had the Philadelphia chromosome.

Of 8 patients resistant to second generation tyrosine kinase inhibitors, 3 had a complete response with normal blood counts, and 2 achieved the absence of the Philadelphia chromosome.

As research continues, scientists continue to be impressed by how well patients tolerate bosutinib. Given that traditional chemotherapy drugs can have serious side effects, this is good news indeed.

In addition to the fact that bosutinib seems to work in patients whose cancer has become resistant to other therapy, it also causes less severe side effects than the other tyrosine kinases.

This is thought to be because it targets the specific protein in the leukemic cells and not in normal cells. Bosutinib is the only kinase inhibitor shown to target CAMK2G, which is linked to myeloid leukemia cell proliferation.

Acute Myeloid Leukemia or AML is a cancer that begins inside the bone marrow, the soft tissue found inside the bones that is responsible for forming blood cells. Persons with this kind of cancer have abnormal cells in their bone marrow. In AML, there are too many white blood cells called myeloblasts present in the bone marrow, which grow rapidly and take the place of healthy blood cells. The bone marrow which normally helps in fighting infections ultimately stops working, and the person with AML becomes more prone to infections. Furthermore, there is an increased risk of bleeding as the number of healthy blood cells declines.

AML is one of the more common types of acute leukemia in adults. This kind of cancer is rare under the age of 40, and is more prevalent in individuals over the age of 65. It is also more common in men than in women. This disease usually gets worse quickly if left untreated, and often it is difficult for doctors diagnose AML. There are certain risk factors to look for that may cause AML. These factors include smoking, exposure to radiation, chemotherapy, certain chemicals like benzene, genetic predisposition, a weak immune system and previous blood disorders.

Cancer treatment with bosutinib

Cells of many tumors get histone deacetylase (HDAC) hyperactivity and several drugs have been developed that are intended to inhibit HDAC activity. Bosutinib is one of those drugs. It is being investigated for colon cancer, but the main type of cancer that it is used for is leukemia.

Chronic Myelogenous Leukemia (CML) occurs mainly in patients with an abnormal chromosome called the Philadelphia chromosome. The abnormal chromosome causes production of Bcr-Abl protein. This protein is a tyrosine kinase, an enzyme which acts in the bone marrow, where blood cells are made. It causes too many white blood cells to be produced, as well as immature stem cells called blasts. These replace other important cells made in bone marrow, including platelets and red blood cells.

There are other tyrosine kinases. Tyrosine kinases in general regulate protein behavior inside cells by attaching phosphate groups to small molecules or proteins. In the presence of the abnormal Bcr-Abl protein, Abl kinase is unregulated. There are a number of drugs that inhibit tyrosine kinases. What is needed to treat CML is an inhibitor that works mainly on the Bcr-Abl mutation and not on tyrosine kinases needed for normal cells.

Many tyrosine kinase inhibitors have been found and used to treat both CML and ALL (acute lymphoid leukemia). The first of these is called imatinib and is now standard chemotherapy for Philadelphia chromosome positive CML. It is also used in conjunction with other drugs for some patients with ALL. Patients often become resistant to imatinib. Over-expression of specific Src kinases is associated with imatinib-resistant cases of CML. In resistant cases, one of the next generation of tyrosine kinase inhibitors, including nilotinib and dasatinib, might be used for treatment. Imatinib (trade name Gleevec) was FDA approved in 2001, dasatinib (trade name Sprycel) in 2006 and nilotinib (trade name Tasigna) in 2007.

Looking forward, an ongoing study in Florida, Georgia and Iowa is comparing bosutinib to imatinib in newly diagnosed, Philadelphia chromosome positive CML. Wyeth, which makes bosutinib, is the responsible party for the study. It is still recruiting patients, and is expected to run for eight years.

A two-part safety and efficacy study of bosutinib found no apparent relationship between dose and efficacy for some metrics. This may be because the doses tried were so high that response plateaued.. Doctors are still working out the correct dosage for this drug.

Research is still attempting to establish that patients in all phases of Philadelphia positive CML and ALL will derive benefit from bosutinib at or below the maximum tolerated dose.

Anyone interested in more information about bosutinib or the ongoing studies can visit http://clinicaltrials.gov/ct2/home
There is a search engine to find studies of interest.

There are certain factors that affect the chance of recovery of the patients. The prognosis and treatment depend on the age of the patient, past history of blood disorders, history of previous chemotherapy treatments, extent of spread of the cancer at diagnosis and whether the cancer is a recurrence of a prior event. Several tests and procedures are also done to determine how far the cancer has already spread, including ultrasound exams, lumbar puncture and chest x-ray. Treatment of leukemia involves extensive chemotherapy, stem cell transplant and/or radiation therapy. The goal of treatment is to destroy the diseased bone marrow cells and replace them with healthy bone marrow cells from a compatible donor. New treatments continue to be investigated, including use of infant cord blood cells or stem cell research. If the patient’s therapy is successful, additional monitoring and treatment need to be performed on an ongoing basis to make sure the cancer does not recur.

Side Effects of Bosutinib

Common side effects in these studies included nausea, vomiting and diarrhea, which diminished over time. One abstract described the diarrhea as “self-limiting”. Lowered numbers of other blood cells, including platelets, white and red blood cells, were seen in one percent to nine percent of patients. There was also a buildup of fluid in the lungs and organs of 12 patients. But all of these symptoms were less severe than with other tyrosine kinase inhibitors.

One good thing about bosutinib is that it appears even patients with liver damage can tolderate it. Given that heptactic impairment poses such a problem for drug therapy, this is good news indeed. This drug leaves the body a few days after it is ingested.

Although the developers are looking at bosutinib mostly as a possible leukemia treatment, studies have also been launched to look at its efficacy in advanced and metastatic breast cancer as well as advanced or recurrent solid malignancies for which no other effective treatment was available.

Possible signs of leukemia include fever, feeling tired or fatigue, easy bruising or bleeding, shortness of breath, petechiae (flat, pinpoint spots under the skin due to bleeding), weight loss, loss of appetite, abnormal menstrual period in women, bleeding from the nose, bleeding gums, bone pain or tenderness and pale skin rashes or lesions. In diagnosing AML, doctors will perform a variety of tests and examine blood and bone marrow of the person. Some of the tests and procedures used include blood chemistry studies, complete blood count, peripheral blood smear, cytogenic analysis, bone marrow aspiration and biopsy, immunophenotyping and reverse transcription.