The Cancer Chemotherapy Targeting Tyrosine Kinase Biology Essay

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Cancer is the condition in which the cells divide abnormally and without control. These types of cells are called as "Cancer cells". Cancer cells have the capacity to invade other tissues and they can expand to other tissues of the body parts travel through lymph and blood circulation systems. The normal cells have the control over their cell cycle like where to start and where to stop, where as the cancer cells have no control over their cell cycle.

Causes of Cancer?

Cancers are caused by genetic material abnormalities in the transformed cells [1]. By the effects of carcinogens , like radiation, tobacco smoke, infectious agents and chemicals these abnormalities may occur. There are other cancer-promoting abnormalities, which are genetic may randomly occur in the replication of DNA. The cells can acquire the cancerous cell properties by the presence of carcinogens, facing the physical injuries periodically and the environmental conditions like low Oxygen condition such as Hypoxia [2] .

Types of Cancers?

Cancers are many types , They broadly categorized into the following types. Carcinoma, Sarcoma, Leukemia, Lymphoma and myeloma and Central nervous system cancers. Sarcoma is a term to the malignant neoplasm or cancer in which the cells are transformed from the connective tissue [3] , such as cartilage, bone and fat connective tissue , which are originated from the mesoderm of embryo[4]. Carcinoma is a term associate with the malignant tumor which contains Epithelial cells. If a carcinoma focuses to a particular small localized area and that did not invades through basal epithelial membrane is referred as carcinoma In situ. CIS is a pre invasive cancer and it would not be pre malignant property [5].

Cancer targeted organs?

Cancer may target to the different tissues and organs of the body . They may include Breast , Prostrate, Blood , Bone , Lungs, Brain, Throat , Stomach , Intestine, Ovaries, Fallopian tubes, Uterus , Cervix, Testicles, Larynx, Pharynx, Esophagus, Oral cancer, Rectum , Bladder, Skin, colon, Thyroid , Kidney and etc. In blood it has different targets like WBC, RBC, etc. If cancer attacks WBC it is known as Leukemia. Skin cancer is the most probable type of Cancers is in the United States of America[6].

Statistics Regarding Cancer

Cancer occupies the fourth position among all the diseases , About 7.9 millions of people died in the 2007 according to the World Health Organization, it accounts for 13% of total deaths in 2007 [7]. Lung , liver , colon, breast and stomach cancers causes most of the deaths in each year. About 30% of the cancers can be curable. Tobacco is the single most risk factor for the cancer. If it is the same case with the following years , the cancer deaths will reaches to 12 millions in the year 2030. Out of all the countries , the low and middle income countries possess 72% of all the deaths of cancer [8].

Modes of Cancer Treatment

There are five different modes of Cancer treatments currently available. They are


Radiation therapy


Hormonal therapy

Biological therapy


The treatment of disease with the help of drugs, basically by chemicals is known as "Chemotherapy" [9]. The chemicals or drugs which are used in the administration of chemotherapy , mostly targets the fast- dividing cells by obstructing their mitosis. In this process the chemicals may cause hazardous effect on the cells and those type of drugs are called as cytotoxic drugs. The administration of these drugs may cause programmed - cell death by means of apoptosis .

Chemotherapy can be used to cure cancer by destroying the cancer cells in the body, it also used to control the growth of cancer cells inside the body , to prevent spreading of cancer cells to the other parts of the body by means of metastasis and to eradicate completely from the body. Chemotherapy is used more often only to treat cancer to destroy the cancer cells. But sometimes the cancer cells will get resistance against the drugs which are used in the chemotherapy. Hence sometimes it needs a surgery or biological therapy or radiation therapy along with chemotherapy. The drugs which are used in the chemotherapy can make the larger tumors into smaller ones before going to the surgery or radiation therapy. This process of treatment is known as neo-adjuvant chemotherapy. The process in which the drugs can destroy the cancer cells which are remain after radiation therapy and surgery is called as adjuvant chemotherapy. Chemotherapy can be given by injection , topically or by orally. The injection may be Intra venous , intra muscular , intra peritoneal , intra arterial, etc,.

Radiation therapy

Radiation therapy means the exposure of the ionizing radiations on to the tumor cells to kill them. In this therapy the ionizing radiation cause damage to as many cancer cells and may cause damage to near by healthy cells. In this therapy the radiation ionizes the genetic material of tumor cells and it could not allow the tumor cells to grow. There are many types of radiation therapies are currently available to treat different types of tissues or organs those are targeted by tumor cells. They are External radiation therapy , Internal radiation therapy and systemic radiation therapy. Radiation doses are given according to the size of tumor tissue and the advancement of the disease. For this therapy X-rays , gamma rays or proton beams are utilized. Recent studies focuses on the target specific controlled radiation therapy by employing radiolabelled antibodies to the site of action. This process of therapy is known as radio -immunotherapy .

Biological therapy

Biological therapy is as similar as chemotherapy , but biological therapy deals with the immune system like allowing immune cells to fight against cancer cells in the body where as the drugs used in the chemotherapy targets the tumor cells to destroy them and to get rid of the disease. Biological therapy is also called as immunotherapy or biotherapy. Some antibodies , cytokines and other cells may produced to treat cancer. These are known as Biological response modifiers . BRMs consists of interleukins , interferons , vaccines , antibodies and other immune cells. By employing biological therapy we can stop the uncontrolled growth of tumor cells , control the metastasis of tumor cells to the whole body and we can make the tumor cells recognizable to the immune cells.


Surgery is also one of the major therapies of cancer treatments. It includes the excision of the tumor tissue from the site of disease. Surgery may be employed along with chemotherapy or radiation therapy , it gives good results than alone.

Side effects

Loss of craving , weakness , premature menopause , loss of hair , lesions in mouth , decreased immunity , and sensitive to smaller allergic reactions , may take longer time to recover , painful processes , may cause potential damage to heart, liver, kidney. Post chemotherapy cognitive impairment may occur due to damage of cell in the brain is also called as chemo brain [10] . Radiation therapy side effects includes damage to the epithelial cells, edema, impotency, fibrosis, dryness, cancer, heart disease, and depression of immune system, epilation, cell count decrement, pain while passing urine, sore throat, cough, fever and breathlessness, bone pain, headache, diarrhea, high blood pressure, rashes, flu like symptoms, blood clots, bleeding for long time due to platelet break off, constipation, difficulty in swallowing, loss of bowel control and etc,.

Cancer Treatment Targeting tyrosine Kinase

The reason for targeting tyrosine kinase in cancer is due to its involvement in regulation of various cellular processes like cell growth , differentiation , migration and apoptosis these contribute to the tumor formation and its progression. In cancer cells the activated kinases contribute to the progression towards malignancy [11]. Hence we can potentially inhibit the progression of tumor cells towards malignancy in which the cell growth is carried out by these activated kinases. Recent studies indicate that the usage of tyrosine kinase targeted drugs offers increased protection against tumor progression in tyrosine kinase mediated cell growth. The tyrosine kinase targeted drugs are Imatinib, it acts against BCR-ABL and other kinases, Gefitinib, it acts against the epidermal growth receptor EGFR, Erlotinib, Cetuximab and Trastuzumab, it acts against HER2/ErbB2 receptor.

Imatinib - Chronic Myelogenous leukemia (CML)

The leukemic cells which are isolated from the Chronic Myelogenous Leukemia patients exhibits a characteristic reciprocal translocation between the 9th and 22nd chromosomes, and known as Philadelphia Chromosome (Ph). The bcr gene and c-ble gene will get in closer while in the translocation of these chromosomes at molecular level. A non receptor tyrosine kinase produced by the gene c-able and the oncoprotein was created by the genetic fusion , and BCR-ABL continuously with the active tyrosine kinase activity.

The pluripotent hemopoetic stem cells will undergo expeditious clonal expansion by BCR-ABL. The unregulated BCR-ABL kinase activity is enough cause leukemia and creating it as an exemplary therapeutic target. It was found that the expansion of BCR-ABL exhibiting cells and their capacity to form tumors in mice was potently inhibited by Imatinib (STI-571) [12]. Imatinib tyrosine inhibitor shows minimal side effects in patients. All most all the patients showed the hematological responses to that of Inhibitor [13]. In the cells of bone marrow of half of the patients had a considerable level of reduction in Ph - Chromosome positive. And several patients had a complete cytogenetic exemptions.

Imatinib- tyrosine kinase inhibitor blocks the other kinases activity like c-kit receptor and platelet -derived growth factor receptor (PDGFR). The patients who are with the tumors which expresses the permanently activated forms of c-kit receptor (in gastro intestinal stromal tumors) are non responsive to the traditional chemotherapy , showed a superior response to Imatinib [14]. Imatinib shows clinical activity in other cancers associated with the PDGFR modifications.

Trastuzumab (Herceptin)

Trastuzumab (Herceptin) - It acts against the HER2/ErbB2 receptor. Excessive expression of HER2 leads to the malignant alterations in epithelial cells of mammary gland. About 25% of intrusive primary breast cancer shows HER2 gene augmentation. The growth of HER2 excessive expressing cells can be inhibited by Trastuzumab, which adhere to the extra cellular part of HER2 receptor. And Herceptin is a monoclonal antibody that developed from the human cells [15]. In recent studies shows that Herceptin causes the considerable advantage for patients having HER2 positive metastatic breast cancer [16]. The post operative administration decreases the local and the distant repetition by half [17][18]. And Increases the rate of survival rate when in was given along with that of chemotherapy by one-third [18].

Anti - EGFR Therapies

Erlonitib and Gefitinib are the Anti -EGFR that are small molecule inhibitors tyrosine kinase activity receptors. These acts against the Epidermal Growth Factor Receptor. Both EGFR (HER1) and HER2 has the highest degree of similarity. Two classes of Anti- EGFR drugs are available currently. And both obstruct the major signal transduction pathways like MAPK (Mitogen-activated protein kinase ) , P13K/Akt and Jak/Stat pathways. These two classes of drug show an enhanced growth inhibitory effect on cancer cells in vitro [19] . Cetuximab effective in patients whose illness has become obstinate to chemotherapy [20] . EGFR Tyrosine kinase inhibitors increases the endurance in the patients with advanced pancreatic cancer [21] , and the outcomes have been observed in globlastoma [22] .

The tyrosine kinase inhibitors are effective over ErbB receptors. Anti - EGFR Monoclonal Antibodies draw out Antibody Dependent cell cytotoxicity . And it causes tumor cells to be more exposed to the charge by the immune system. Anti - EGFR therapies for Non - small cell lung cancer includes Tyrosine kinase inhibitors acclaim for treating NSCLC patients. Tyrosine kinase inhibitors enhances the overall survival of the patients who failed in the second line of chemotherapy [23 ]. And also enhances the survival of extreme stage pancreatic cancer patients.

Acquired Resistance to Imatinib

Despite early success to this drug in the early stages, it was found later that considerable drug resistance is developed by the majority of drug responding patients. Resistance mutations were observed in kinase domains of BCR-ABL in Chronic Myelogenous leukemia (CML) and Kit & PDGFR in Gastrointestinal stromal tumors (GIST) [24].

Acquired Resistance to Erlotinib & Gefitinib:

Patients treated with these Tyrosine Kinase Inhibitors develop 2o EFGR mutations in Non-small cell lung cancers(NSCLC). K-Ras mutations found in smokers is correlated with resistance to EFGR inhibitors.

Acquired Resistance to Trastuzumab (Herceptin):

Although the acquired resistance in patients treated with Herceptin is not well defined, it is assumed that the possible mechanism would be due to the loss of PTEN function and absence or loss of antibody binding domain of the receptor.

Acquired Resistance in Second generation Tyrosine Kinase Inhibitors:

The activityof imatinib in CML and GIST, trastuzumab in breast cancer, and anti-EGFR agents in NSCLC has validated the concept that certain tumors are ''oncogene dependent'' [25].A clinical strategy can be developed by random testing of imatinib across tumor types without focusing on Bcr-Abl- and c-Kit-dependent cancers, or of trastuzumab in non-HER2 amplified tumors, but the success would be little.The second-generation inhibitors that are effective against tumors with acquired drug resistance illustrate the potential of mutation-specific therapies, but they also raise the question of whether secondary resistance might be avoided or delayed by the combined administration of tyrosine kinase inhibitors up front instead of a sequential approach. The possible answer would come from trials testing combinations of agents directed at a single tyrosine kinase.

It is very complex to determine whether a malignant tumour is entirely dependent on an abnormal protein kinase or a signaling pathway because of its genetic complexity. there is always a considerable interference between the different metabolic pathways, a survival strategy employed by the cancer cell.

Upcoming researches on molecularly targeted therapies may highlight on the establishment of new drugs and drug targets, enhanced selection of tumors sensitive to these drugs, and the logical design and optimization of consolidated therapies. The recent discoveries will help transform oncology to one in which treatment methods are depend on mechanistic approach that fruitfully accommodate molecular biology, pathology, imaging, and clinical research.

References and notes

^ Kinzler, Kenneth W.; Vogelstein, Bert (2002). "Introduction". The genetic basis of human `cancer (2nd, illustrated, revised ed.). New York: McGraw-Hill, Medical Pub. Division. p. 5. ISBN 978-0-07-137050-9.,M1.

^ Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E (September 2004). "Hypoxia and defective apoptosis drive genomic instability and tumorigenesis". Genes & Development 18 (17): 2095-107. doi:10.1101/gad.1204904. PMID 15314031

ï‚· ^ sarcoma at Dorland's Medical Dictionary

ï‚· ^ MeSH Sarcoma

^ Banerjee AK. Preinvasive lesions of the bronchus. J Thorac Oncol 2009;4:545-51.

National Cancer Institute - Common Cancer Types (

^ WHO (2007). "Cancer".


ï‚· ^ chemotherapy at Dorland's Medical Dictionary

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