A 37-year-old man is diagnosed with Philadelphia chromosome-positive (Ph+) chron

Question

A 37-year-old man is diagnosed with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

a. What is the molecular mechanism that makes this kind of cancer?(1/2 page)

b. What is the first-line treatment for CML and what is the rationale for this pharmacotherapy?(1/4 page)

c. What are the mechanisms of resistance to imatinib pharmacotherapy of CML?(1/4 page)

d. What other cancers and diseases are effectively treated with imatinib?(1/4 page)

e. What are the common and important side effects of therapy with imatinib(1/4 page)

Explanation / Answer

a. Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) is a form of bone marrow and blood cancer. People who got this cancer generally produces excessive amount of daaged or immature white blood cells from bone marrow. In Philadelphia positive chromosome, an abnormal gene, BCR-ABL1 i responsible for the formation of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). In principle, for the pateint with this cancer chromosome no 9 and 22 get broken abd interchanged position. In normal situation, BCR gene is present on chromosome 22 whereas, ABL1 gene is present on chromosome 9. But in pateints with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) this two chromosome get broken and interchanged place to by reciprocal translocation mechanism and produce a defective phailadelphia chromosome. This gene is resposible for the production of a default protein , which is also called as BCR-ABL1. In healthy individual, BCR-ABL1 protein will produce white blood cell from bone marrow as requred. However, in pateints with this particular type of cancer, the deformed BCR-ABL1 protein can not control any more the white blood cell production. This lead to large amount of white bllod cell which can cover the healthy normal blood cell in the body.

b. The first line of tratment of chronic CML includes the drug is Imatinib. Imatinib is found to inhibit BCR-ABL1 tyrosine kinase. Tyrosine kinase is required for several process like cell growth, apoptosis and metabolism.In pateints with CML, the protein BCR-ABL1 has been found to be expressed constituvely. The tyrosine kinase inhibitor like imatinib has been designed in such way that it can block the function of BCR-ABL1 protein.

c. Although, imatinib has been widely used in pateints with CML, however, in some instances, imatinib can not be fully affective agaist CML and a resistance mechanism against BCR-ABL1 . It has been found that there can be a mutation on the ABL-kinase-domain. As a result, imatinib can not inhibit the expression of BCR-ABL

d. imatinib is also used for certain other type of cancers like gastrointestinal stromal tumors , or skin cancer type dermatofibrosarcoma protuberans.

e. Side effects of imatinib includes symptoms like-

diarrhea,

pain in muscle,

vomiting

headache

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