Drug Treatment of Hematopoietic Malignancy

We are going to talk in this sheet about drug treatment of Hematopoietic malignancy In the last lecture we have talked about cell cycle and the drugs that work on each stage of the cell cycle . Also, the figure below is related to the last lecture and it is talking about Anticancer drugs targets, which are :1-Nucleotide synthesis / 2- DNA synthesis / 3- RNA synthesis / 4- Protein synthesis 5- Cellular division process 1|Page Drugs used in leukemias and Lymphomas :- ( DON’T MEMORIZE KNOW RETURN BACK TO THEM ) Antitumor antibiotics: 1-Bleomycin / 2-Doxorubicin, Daunorubicin Antimetabolites: 1- Cladribine / 2-Cytarabine / 3- Methotrexate Alkylating agents: 1-Busulfan / 2-Cyclophosphamide, ifosfamide / 3-Procarbazine Microtubule inhibitors: 1-Vincristine / 2- Vinblastine Miscellaneous: 1-Hydroxyurea / 2- Imatinib, dasatinib / 3-Rituximab A- Antitumor Antibiotics: These antibiotics originally have anticancerous effect; they might have effect on hematopoietic as well as non-hematopoietic malignancies and other cancerous conditions Drug name Bleomycin Doxorubicin, Daunorubicin Mechanism of action Induces free radical formation which causes breaks in DNA strands. Intercalates into DNA, preventing RNA synthesis. Hematopoietic malignancies and other 1-Testicular cancer conditions affected by this 2-Hodgkin lymphoma Drug Adverse effects 2|Page 1-Solid tumors 2-leukemias 3-lymphomas. 1-Pulmonary fibrosis ( VIP) Cardiotoxicity (dilated 2-Flagellate erythema 3-Minimal myelosuppression (and this is good because it avoids severe myelosuppression since many anticancer drugs cause severe myelosuppression ) cardiomyopathy), myelosuppression, alopecia (many anticancer drugs causes alopecia , but it is reversible and not serious as cardiotoxicity and myelosuppression ) Note:Dexrazoxane (iron chelating agent) is used to prevent cardiotoxicity, but it decreases the effect. Note B- Antimetabolites Drug name Mechanism of action Hematopoietic malignancies and other conditions affected by this drug 3|Page Cladribine Cytrabine Methotrexate Purine analog —> multiple mechanisms (e.g. inhibition of DNA polymerase, DNA strand breaks). Pyrimidine analog ->DNA chain termination. Folic acid analog that competitively inhibits dihydrofolate reductase => decreases dTMP => decreases DNA synthesis. -At higher concentrations, inhibits DNA Polymerase. 1-Cancers:1-Leukemias A-leukemias (ALL: Hairy cell leukemia. (AML: Acute Acute lymphocytic myeloid leukemia) leukemia) 2-lymphomas. B-lymphomas C-choriocarcinoma (malignant tumor of the placenta) D-sarcoma 2- Other medical applications:A-ectopic pregnancy B-medical abortion (with misoprostol) C-rheumatoid arthritis D-psoriasis E-IBD (Inflammatory Bowel Disease) F- vasculitis. Adverse effects 1Myelosuppression 2- Nephrotoxicity 3- Neurotoxicity. 1-Myelosuppression, which is reversible 1with leucovorin Myelosuppression “rescue.” with megaloblastic 2-Hepatotoxicity. anemia. 3-Mucositis (e.g. mouth ulcers). Remember :4-Pulmonary fibrosis. CYTarabine causes 5-Folate deficiency, panCYTopenia. which may be teratogenic (neural tube defects) without supplementation. 6-Nephrotoxicity. C-Alkylating agents Drug name Mechanism of action 4|Page Busulfan Cross-links DNA. Procarbazine Cyclophosphamide Ifosfamide Cell cycle phase– nonspecific alkylating agent, mechanism not yet defined. Cross-link DNA at guanine. * Require bioactivation by liver. Hematopoietic malignancies and other conditions affected by this drug Used to ablate patient’s bone marrow before bone marrow transplantation. Bone Marrow transplant is used in numerous applications (in cancers, Bone marrow defects, problems in hemoglobin synthesis as in thalassemia …etc) so before we transplant the new bone marrow in the patient we should ablate his own bone marrow totally!! And this is done using this agent. 1-Hodgkin lymphoma 2-leukemia 2- brain tumors. 3-lymphomas 4-rheumatic disease (e.g. SLE -Systemic Lupus Erythematous -, granulomatosis with polyangiitis). 1-Bone marrow suppression Adverse effects 1-Severe myelosuppression (in almost all cases) 2- Pulmonary toxicity, 2-pulmonary fibrosis 3-Leukemia, 34-Disulfiram-like hyperpigmentation reaction ( this reaction is used in treating alcoholism; alcoholic patients are given a drug called Disulfiram 5|Page 1-Solid tumors 1-Myelosuppression 2- SIADH (Syndrome of inappropriate antidiuretic hormone secretion) 3-Fanconi syndrome (ifosfamide) 4-Hemorrhagic cystitis and bladder cancer ( VIP ) , prevented with Mesna (sulfhydryl group of Mesna and then when binds toxic they accidentally or metabolites) and intentionally ingest adequate hydration alcohol, a reaction (called Disulfiram reaction) takes place producing bad effects, thus the patient won’t like alcohol due to the effect of this reaction ) . Notes *A nitrogen mustard D-Microtubule inhibitors Drug name Vincristine / Vinblastine -plant products- Mechanism of action Vinca alkaloids bind β-tubulin and inhibit its polymerization into microtubules => prevent mitotic spindle formation (M-phase arrest). Hematopoeitic malignancies and other conditions affected by this drug 1-Solid tumors 2-leukemias 3-Hodgkin lymphomas 4- non-Hodgkin lymphomas Adverse effects Vincristine: neurotoxicity (areflexia (diminished reflexes) , peripheral neuritis), constipation (including paralytic ileus). It Crisps the nerves. Vinblastine: bone marrow suppression. It Blasts the bone marrow. 6|Page E-Miscellaneous Drug name Hydroxyurea Mechanism of action Inhibits ribonucleotide reductase => DNA Synthesis (Sphase specific). Hematopoietic 1-Myeloproliferative disorders (e.g., CML, malignancies and other polycythemia vera) conditions affected by this 2-sickle cell (increases HbF). drug Adverse effects Severe myelosuppression. F- Tyrosine kinase inhibitors Drug name Imatinib / Dasatinib Mechanism of action Inhibitor of Tyrosine Kinase domains of :1)Bcr-Abl oncoprotein (encoded by Philadelphia chromosome fusion gene in CML) 2)PDGFR (platelet-derived growth factor receptor ) 3) and c-kit (common in GI stromal tumors). Hematopoietic 1-CML ( Chronic Myelogenous Leukemia ) malignancies and other 2-GI stromal tumors (GIST) conditions affected by this drug Adverse effects 7|Page Safe drugs but can cause fluid retention (giving diuretics). F- Monoclonal antibodies Drug name Rituximab Mechanism of action Monoclonal antibody against CD20, which is found on most of B-cell neoplasms. Hematopoietic malignancies and other conditions affected by this drug 1-Non-Hodgkin lymphoma 2-CLL (chronic Lymphocytic leukemia). 3-ITP (immune Thrombocytopenic purpura). 4-rheumatoid arthritis. Adverse effects Carry the risk of progressive multifocal leukoencephalopathy (by reactivation of JC virus ; JC virus remains dormant in the central nervous system and becomes activated after giving this drug) and other Opportunistic infections, also Hepatitis B reactivation (hepatitis B reactivation is very serious and it could be more dangerous than the tumor itself) * Must screen for Hepatitis B and C before giving Rituximab 8|Page To remember the adverse effects of the drugs the figure below simplifies these effects:- 9|Page