Dalton’s Lymphoma as a Murine Model for Understanding the Progression and Development of T-Cell Lymphoma and Its Role in Drug Discovery

Mouse models are irreplaceable tools for the study of carcinogenesis and the availability of rodent models have enabled rational screening of drugs. Hematological malignancies have been extensively studied in mouse models and broad range of lymphoid neoplasms has been reported in laboratory mice, occurring either spontaneously or after induction with radiation, chemicals or infection of newborn mice with leukemogenic viruses. Lymphomas are tumors that generally respond well to traditional therapies such as chemotherapy and radiotherapy. Dalton’s lymphoma is a transplantable T-cell lymphoma of spontaneous origin in thymus of murine host and has emerged as an interesting model for cancer research, because of its usefulness in pre-clinical system for evaluating new or known drugs in the treatment of various cancers and in drug discovery development process. Review Article Dalton’s Lymphoma as a Murine Model for Understanding the Progression and Development of T-Cell Lymphoma and Its Role in Drug Discovery Raj Kumar Koiri1*, Aditi Mehrotra2 and Surendra Kumar Trigun2 1Biochemistry Lab, Department of Zoology, Dr. Harisingh Gour Central University, Sagar 470003, Madhya Pradesh, India 2Biochemistry & Molecular Biology Lab, Department of Zoology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India Dates: Received: 02 January, 2017; Accepted: 31 January, 2017; Published: 01 February, 2017 *Corresponding author: Raj Kumar Koiri, Biochemistry Lab, Department of Zoology, Dr. Harisingh Gour Central University, Sagar 470003, Madhya Pradesh, India, Tel: +91-9179562075; E-mail:


Introduction
The identifi cation of novel clinically active agents has been central to progress in cancer chemotherapy. Animal models in general, and especially mouse models, are irreplaceable tools for the study of carcinogenesis and the availability of rodent models have enabled rational screening of drugs.
The mouse shares anatomical, immunological and genomic similarities with humans and is the most accessible model system [1]. A goal in the studies of mouse lymphomas is to identify the human counterpart to the studied disease in order to understand the pathogenesis and evaluate new treatments for the disorder in humans. Hematological malignancies have been extensively studied in mouse models and broad range of lymphoid neoplasms has been reported in laboratory mice, occurring either spontaneously or after induction with radiation, chemicals or infection of newborn mice with leukemogenic viruses [2]. Lymphomas are tumors that generally respond well to traditional therapies such as chemotherapy and radiotherapy. However, for the patients that do not respond, or when tumors recur, new therapeutic approaches are warranted. Pre-clinical studies are important to screen the new compounds for potential effect against the disease. Murine lymphoma models are relatively inexpensive and easy to maintain; thus proven to be a useful tool in studies of lymphomagenesis and lymphoma treatment. Preclinical activity of an anti-tumor agent in a relevant in vivo system is a sine qua non for clinical testing. Multiple studies have been undertaken to assess the ability of preclinical animal activity to predict antitumor response in man.

Lymphoma: Hodgkin's lymphoma and non-Hodgkin's lymphoma
Lymphomas are a large and heterogeneous group of malignant diseases of lymphoid tissue, consisting of 70 different subtypes recognized within the new World Health Organisation (WHO) IV lymphoma classifi cation system [3].
White blood cells (leukocytes), which constitute the cells of the immune system, are divided into lymphoid cells (T and B lymphocytes) and myeloid cells (granulocytes, monocytes and macrophages). Lymphoma is the broadest category of a family of related blood cancers, involving a group of cells, called the lymphocytes, which in turn make up the lymphatic system-a part of the immune system. It is a type of blood cancer that occurs when lymphocytes, which are white blood cells that help to protect the body from infection and diseases starts behaving abnormally, causing them to divide faster and may live longer than they are supposed to. Lymphoma may Citation: Koiri  develop in many parts of the body, including the lymph nodes, spleen, bone marrow, blood and sometimes, non-hemopoetic tissues are also involved. Malignant lymphoma is the generic term given to tumors of the lymphoid system. These tumors are divided into two major categories: Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL); named after Thomas Hodgkin, who fi rst described Hodgkin's lymphoma in 1832 [4,5]. Hodgkin's lymphoma is characterized by the presence of an abnormal cell type, Reed-Sternberg cell (a B lymphocyte) which expresses B cell markers, such as CD20, but is absent in the second type of lymphomas, therefore referred to as non-Hodgkin's lymphomas (NHL) [6,7]. Non-Hodgkin's lymphoma is a heterogeneous group of malignancies characterized by an abnormal clonal proliferation of T cells, B cells, or both [8].
Both types can start in the lymphoid tissue (also called lymphatic tissue) and can spread to other organs. Lymphoid tissue is found in many places throughout the body, including lymph nodes, the thymus (found behind the chest bone and in front of the heart), the spleen (on the left side of the abdomen next to the stomach), the tonsils and adenoids, in the bone marrow, and scattered within other systems such as the digestive and respiratory systems. Patients with lymphoma when physically examined presents the symptoms of lymphadenopathy, splenopathy, enlarged liver and kidneys, pleural exudate, oedema, abdominal swelling, somnolence, tachypnea and tachycardia [9]. Lymphadenopathy can cause compression of other tissues like the ureter or spinal cord. Rapid tumour growth in aggressive lymphomas causes severe illness.
Lymphomas can transform from non-aggressive lymphomas to aggressive lymphomas and therefore high-grade malignancies.
Radiotherapy for treatment is not directly useful, and therefore patients receive chemotherapy, primarily Rituximab to CHOP (a combination of cyclophosphamide, vincristine, doxorubicin and prednisolone), followed by radiotherapy [8]. Each  Table 1.

Incidence of Non-Hodgkin's lymphoma
In India among the males aged between 15-29 years, the three most common cancers are leukemia, lymphoma, and central nervous system tumors. Non-Hodgkin's lymphoma is the 11th most common cancer in terms of incidence [10]. It is most frequent in high income countries, with rates more than twice those of middle-to low-income countries. It is usually fatal, with a 5 year survival rate of less than 35 percent. It is not a single cancer, but rather a wide group of cancers (including entities such as Burkitt's lymphoma and diffuse large B-cell lymphoma), each with a distinct geographical distribution, development path, age profi le and prognosis. The incidence rates of Non-Hodgkin's lymphoma have risen dramatically in the last 30 years, particularly in developed countries, including Western Europe, North America and Australia [11]. Non Hodgkins Lymphoma, which was once considered rare, has slowly grown to the fi fth most common cancer (incidence of 19.1 per 100,000 in USA) in the world [12]. About 65,500 cases of non-Hodgkins lymphoma were expected to be diagnosed in the United States in 2010 [13]. Non-Hodgkins lymphoma occurs in individuals at virtually all ages, but it is uncommon in children.
The incidence of NHL increases with age [13]. In the 20-to 24- In India its incidence is on the upsurge with the current fi gure standing at 5.1 per 100,000 in urban registries. The incidence of lymphomas is still growing, and in the future this group of malignancies will form a quantitatively remarkable subtype of malignant diseases. In many lymphoma subtypes, the prognosis is good and the treatment results are continuously improving due to new treatment modalities. However, some lymphoma patients still succumb to their disease and certain most aggressive subtypes of lymphoma are often beyond curative treatment [14][15][16][17]. NHL being a systemic disease, a systemic approach like chemotherapy has been considered to be more appropriate and is treated with chemotherapy, and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage of the disease [18].

T cell lymphomas
Lymphoma is a malignancy of the immune system. In

Daltons Lymphoma
Daltons lymphoma are widely used as interesting model for cancer research, because of its usefulness in pre-clinical system for evaluating new or known drugs in the treatment of  T-large granular lymphoproliferative Positive for CD3, CD7, CD8 but negative for CD4, CD5 and CD30

Mycosis Fungoides
Positive for CD3, CD5 and CD7 but negative for CD4 Cutaneous ALCL (Anaplastic large cell lymphoma) Positive for CD3 and CD30 but negative for CD8 Hepatosplenic T-cell lymphoma Positive for CD3 and CD7 but negative for CD4, CD5, CD8 and CD30 Angioimmunoblastic T-cell lymphoma Positive for CD3 and CD5 but negative for CD7 and CD30 Enteropathy associated T-cell lymphoma Positive for CD3, CD5 and CD7 Adult T-cell leukemia/lymphoma Positive for CD3 and CD5 but not for CD7 Citation: Koiri  various cancers. Dalton's lymphoma is a transplantable T-cell lymphoma of spontaneous origin in thymus of murine host [25,26]. During the late tumour bearing stages, DL growth has been shown to be associated with a concomitant inhibition of humoral and cell mediated immune responses involving the abrogated functions of macrophages, B and T cells [27,28] and with an involution of thymus with a massive depletion of immature CD4+CD8+ and mature CD4+CD8and CD4 -CD8+ thymocytes by the process of apoptotic cell death resulting in an alteration in the distribution of T-cell sub populations in the thymus [29]. Immunophenotypic characterization of the lymphoma has revealed it to be of T-cell origin with expression of CD4 and/or CD8 and T-cell receptor (TCR) . Due to effective biodistribution and multimodal cellular actions, during recent past, ruthenium and certain other metal complexes like platinum, copper and gold have drawn much attention as next generation anticancer agents [34,35]. In this respect Dalton's lymphoma has been successfully used to evaluate the anticancer effect and subsequently the mechanism of action of newly synthesized metal complexes of ruthenium [36][37][38], platinum [39], copper [40] and gold complexes.

T-cells obtained from
Recently Sriram et al., 2010, has demonstrated the antitumor activity of silver nanoparticles using Dalton's lymphoma ascites as a tumor model [32].
Activation of p53 mediated glycolytic inhibition-oxidative stress-apoptosis pathway in Daltons lymphoma has been reported by a ruthenium (II)-complex containing 4-carboxy N-ethylbenzamide [57]. Thus, Dalton's lymphoma has emerged as an important murine model for understanding the progression and development of T-cell lymphoma and is playing an important role in drug discovery and development.