Bosutinib - new chemotherapy agent for leukemia and other cancers
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 in the United States necessary to eventually obtain 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.
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.
In Jan 2012 the drugmaker Pfizer submitted a New Drug Application to the FDA for treatment of Ph+ chronic myeloid leukemia.