Myelogenous leukemia and two chemotherapeutic agents

Traditional cancer therapy targets rapidly dividing cells to prevent malignant mitosis. Some of these drugs used in traditional cancer therapy, such as cisplatin, show limited specificity for cancerous cells, and instead affect diverse cell populations in the body, such as hematopoietic stem cells (HSC’s) in the bone marrow, skin cells, and gastrointestinal lining. Cisplatin is used for its ability to crosslink DNA by forming chemical bonds between nucleotides on complementary strands. Crosslinks in the DNA disrupt DNA replication and cell division. This gives cisplatin its limited specificity for cancer cells, since cancer cells tend to be replicating DNA and dividing more rapidly than most other cells in the body.

Recently, cancer therapy has targeted a mutant kinase protein known as Bcr-Abl. This fusion protein is a product of a mutation known as the Philadelphia chromosome, which occurs when chromosomes $9$‍ and $22$‍ undergo a reciprocal translocation. Unlike the “normal” product, Abl, Bcr-Abl is constitutively active. Bcr-Abl is involved in signal transduction pathways that lead to the activation of various downstream effector proteins within the cell. It influences both cell division and cell migration. Since cancer cells rapidly divide and undergo increased migration as they metastasize, Bcr-Abl is an excellent target for anti-cancer drugs.

A new chemotherapeutic agent, called imatinib, is a small molecule that functions as a highly specific inhibitor of Bcr-Abl. Imatinib is part of a larger family of tyrosine kinase inhibitors (TKI’s), and it competes with ATP for a binding site on Bcr-Abl. Imatinib is a very effective treatment option for patients with chronic myelogenous leukemia (CML), who most often harbor a Philadelphia chromosome. CML involves the proliferation of myeloid progenitor cells (which eventually give rise to a subset of white blood cells) deriving from the bone marrow.

Figure 1: The Philadelphia chromosome is caused by reciprocal translocation of a segment from chromosome $9$‍ and a segment from chromosome $22$‍. This situates the gene Abl, indicated by red circles, adjacent to the gene Bcr, indicated by yellow circles, resulting in the fusion protein Bcr-Abl.

Figure 2: Activity of Bcr-Abl was measured based on its hydrolysis of ATP. The rate of reaction is shown as a function of ATP concentration in the presence and absence of imatinib.