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 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.