An asymptomatic 66 year-old man has a routine complete blood count which reveals a leukocytosis of 50,000 white blood cells per microliter. On fluorescent in situ hybridization assay, he is found to have the Philadelphia chromosome in peripheral blood mononuclear cells, and he is diagnosed with chronic myelogenous leukemia. Which of the following is the mechanism of action for the most effective initial drug therapy for this disease?
An antibody that binds to and inhibits Her2/neu on the cell surface.
An antibody that binds to and inhibits CD20 molecules on the surface of B cells.
A small molecule that binds to and inhibits the kinase domain of the BCR-Abl protein.
A small molecule that binds to and inhibits the kinase domain of the epithelial growth factor receptor (EGFR).
A molecule that binds to tubulin dimers and hence inhibits the assembly of microtubules during mitosis.
Correct answer
A small molecule that binds to and inhibits the kinase domain of the BCR-Abl protein.
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correct answer: C
The answer is C. The patient with Philadelphia chromosome-positive CML should first be treated with imatinib (Gleevec), which is a small molecule tyrosine kinase inhibitor that binds to the BCR-Abl protein. It inhibits the protein by binding its kinase domain and decreasing the protein’s affinity for ATP. This protein is the result of a chromosomal translocation occuring in CML which fuses chromosomes 9 and 22 and leads to production of an abnormal oncogenic protein, BCR-Abl. This drug has also proven to be effective in some gastrointestinal stromal tumors (GIST) that express mutated c-Kit protein.
Choice A is incorrect; this choice describes trastuzumab (Herceptin) which is commonly used in breast cancers that overexpress Her2/neu (also known as ErbB2).
Choice B is incorrect; this choice describes rituximab which is sometimes used in B cell lymphoma and other diseases.
Choice D is incorrect; this description is true of both gefitinib (Iressa) and erlotinib (Tarceva) and these drugs are sometimes used in non small-cell lung cancers.
Choice E is incorrect; this choice describes vincristine, a vinca alkaloid which is usually part of multi-drug regimen for certian cancers, usually non-Hodgkin’s lymphoma.