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Toxicity and Anti-Tumor Effects of Cytarabine and Doxorubicin on Acute Myeloid Leukemia

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Toxicity and Anti-Tumor Effects of Cytarabine and Doxorubicin on Acute Myeloid Leukemia MQP-BIO-DSA-5013 MQP-BC-DSA-8980 TOXICITY AND ANTI-TUMOR EFFECTS OF CYTARABINE AND DOXORUBICIN ON ACUTE MYELOID LEUKEMIA A Major Qualifying Project Report Submitted to the Faculty of the WORCESTER POLYTECHNIC INSTITUTE in partial fulfillment of the requirements for the Degrees of Bachelor of Science in Biology and Biotechnology and Biochemistry by _________________________ _________________________ Allison Lombardo Elaina Nichols April 30, 2009 APPROVED: _________________________ _________________________ Lucio Castilla, Ph.D. David Adams, Ph.D. Program in Gene Function and Expression Biology and Biotechnology Umass Medical Center WPI Project Advisor Major Advisor ABSTRACT Leukemia develops from the abnormal expansion of leukemic stem cells that have several genetic alterations that prevent these cells from differentiating into normal white blood cells. Acute myeloid leukemia (AML), one of the most aggressive types of leukemia, is characterized by the accumulation of large numbers of abnormal myeloid cells that do not differentiate into functional granulocytes or monocytes during the hematopoiesis process. The goal of this project was to study the anti-tumor effect of chemotherapy drugs Doxorubicin (Doxo) and Cytarabine (Ara-C) as inhibitors of leukemic cells expressing the oncogene CBFB-MYH11 , which causes AML. This was accomplished by testing these drugs for specificity in vitro against rapidly dividing 3T3 cells and slowly dividing ME-1 leukemic cells expressing inv(16). The drugs were also tested in vivo establishing their toxicity in WT mice, and determining their efficacy in a leukemia transplantation mouse model. In vitro it was determined that Doxo and Ara-C affect the cell cycle of rapidly proliferating 3T3 cells, but have a lesser impact on slower dividing ME- 1 cells. In vivo WT mice can tolerate up to 10 doses of 6 mg/kg/every other day of Doxo, and 27 doses of 200 mg/kg/day of Ara-C. Leukemic mice treated with chemo drugs 4 weeks after transplantation survived thirty nine days with treatment. However, mice treated only 1 week after transplantation survived only nineteen days with treatment. Our research shows that two important factors in decreasing the toxicity and increasing the efficacy of AML treatment are the amount of recovery time post irradiation and the concentration of drug dose. These therapeutic techniques may be used to expand our treatment options for AML. 2 TABLE OF CONTENTS Signature Page ………………………………………………………………………. 1 Abstract ……………………………………………………………………………… 2 Table of Contents ……………………………………………………………….…… 3 Acknowledgements ………………………………………………………………….. 4 1.0 Background ……………………………………………….…………………….. 5 2.0 Project Purpose …………………………………………………………………. 22 3.0 Methods ………………………………………………………………………… 23 4.0 Results ………………………………………………………………………….. 32 5.0 Discussion ……………………………………………………………………… 57 6.0 Bibliography …………………………………………………………………… 63 3 ACKNOWLEDGEMENTS This project was completed in the Gene Function and Expression Department at the University of Massachusetts Medical School under the direction of Dr. Lucio Castilla. We would like to thank Dr. Lucio Castilla for allowing us to work in his lab and for his help and guidance throughout the duration of this project. There are several people that we would like to recognize for their help in the development of our project. First, we would like to thank Dmitri Madera for all of the time and effort he put in helping us with our MQP. You have been a great mentor to us and we appreciate your patience teaching us the necessary techniques to accomplish this project. In addition, Svetlana Gornostaeva and Liting Xue provided support and a helping hand in the lab throughout the year. Finally, we would like to thank Dave Adams for his continuous guidance and encouragement. We sincerely appreciate the direction you provided for this project, your help editing the final report. 4 1.0 BACKGROUND Leukemia is a malignant disease that affects the bone marrow and blood. Currently there is an estimated 231,461 people in the United States living with leukemia (Leukemia Facts and Statistics, 2009). The most common type of adult leukemia is acute myeloid leukemia (AML). Approximately 13,290 Americans were diagnosed with AML in 2008, and 1 out of every 5 children with leukemia were diagnosed with AML (Leukemia Facts and Statistics, 2009). Despite these intimidating statistics, successful treatment options are available for patients diagnosed with AML. One of these options is chemotherapy, which aims to kill as many dividing cells as possible and, over time, return blood cell counts to normal levels. This MQP report will focus on the toxicity and anti-tumor effects of two first line chemotherapy drugs, Cytarabine and Doxorubicin, in AML mouse models and cell lines . 1.1 Hematopoiesis Blood cell formation arises from bone marrow stem cells, a process known as hematopoiesis. The bone marrow contains immature cells called hematopoietic stem cells (HSC) that will eventually mature into the cellular components of blood. The two main characteristics of HSCs are their self-renewal capabilities and their ability to differentiate into a variety of specialized cells. There are two different types of HSCs: one type is a long-term stem cell, which is self renewable over a long period of time. The second type is referred to as short-term stem/progenitor or precursor cell. These cells are immature cells, with reduced self renewal capacity, that are precursors to a fully differentiated cell of the same tissue type (Hematopoietic Stem Cells, 2009). While these progenitor cells are capable of proliferating, they do have a 5 limited ability to differentiate into more than one cell type. In normal blood cell development (Figure 1), HSCs develop and differentiate into myeloid or lymphoid progenitor cells, which undergo differentiation into red blood cells, platelets, and white blood cells. The pluripotent progenitor cell is the precursor for the multi-potential progenitors, the myeloid progenitor cells and the lymphoid progenitor cells. The myeloid progenitors (diagram left side) are precursor cells for red blood cells, platelets, granulocytes and monocytes. The lymphoid progenitors are precursors for B-lymphocytes, T-lymphocytes, and natural killer cells. Figure 1: Diagram of Normal Hematopoiesis. This figure denotes the differentiation of hematopoietic stem cells into the cellular components of blood, an important process in leukemia (Chronic Lymphocytic Leukemia Treatment, 2008) The process of hematopoiesis can be disrupted, and this can have a devastating impact on the human system. If HSCs do not differentiate into other types of normal stem cells, this can lead to leukemia, which is described in the following section. 6 1.2 Leukemia Leukemia is cancer of the blood characterized by the production of irregular white blood cells in the bone marrow. Leukemia develops from the abnormal expansion of leukemic stem cells that have several genetic alterations that prevent these cells from differentiating into normal white blood cells. These immature leukemic stem cells also have rapidly proliferating cell cycles and usually a resistance to apoptosis. 1.2.1 Acute Myeloid Leukemia While there are many types of leukemia, categorized by the level of maturation of white blood cells and the aggressiveness of the disease, acute myeloid leukemia (AML) is one of the most common types of adult leukemia. It begins in the bone marrow, but in the majority of patients with AML, this cancer spreads quickly to the blood and invades other parts of the body, specifically the lymph nodes, liver, spleen, central nervous system, and testes. AML is characterized by the accumulation of large numbers of abnormal myeloid cells that do not differentiate into functional granulocytes or monocytes during the hematopoiesis process (Bonnet and Dick, 1997). Granulocytes are white blood cells that contain enzymes that destroy microbes. There are three different types of granulocytes: neutrophils, basophils, and eosinophils, distinguished by the size and color of their granules. Monocytes are also white blood cells and form in the bone marrow to become blood-forming monoblasts, which eventually develop into mature macrophages (What is Acute Myeloid Leukemia?, 2007). Macrophages destroy bacteria and can recognize germs to help B-cells create antibodies to fight these cells. The types of blood cells mentioned above are shown below in Figure 2 . 7 Figure 2: Photomicrographs of the Various Types of Normal White Blood Cells. Figure 2A1 is a small lymphocyte, with a platelet in the upper right hand corner. Figure 2A2 shows a large lymphocyte. Figure 2A3 is a neutrophil, figure 2A4 is an eosinophil, figure 2A5 is a monocyte, and figure 2A6 contains two neutrophils and a monocyte, on the left. (Fredrickson and Harris, 2000). 1.2.2 CBFB-MYH11 Gene In the hematopoiesis process of an AML patient, the fusion oncoprotein CBF β-SMMHC (smooth muscle myosin heavy chain) causes the development of pre-leukemia stem cells (PSC) from HSCs, which leads to the emergence of abnormal myeloid progenitors (AMP) that do not exhibit normal myeloid differentiation (Kuo et al, 2006). With additional mutations, AMPs become leukemia stem cells (LSC) that expand into AML. This process is shown in Figure 3 . 8 Figure 3: Development of Acute Myeloid Leukemia. Diagram shows the development of AML from hematopoietic stem cells (Castilla, n.d) Clonal chromosomal abnormalities in blast cells from leukemia patients have shown that AML can develop from chromosomal translocations
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