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.