The main technical problem faced in gene therapy is to find a safe and efficient vector technology for gene transfer

The main technical problem faced in gene therapy is to find a safe and efficient vector technology for gene transfer. cells. Over the last few years, these have been (successfully in several instances) explored as potential targets for cancer directed therapy. This gave birth to the era of targeted therapy. Targeted therapy is defined as a drug or molecule causing tumour cell kill by interacting with predefined target(s) present on malignant cells. Such an approach has obvious advantages. The most important being that it would selectively attack the cell surface molecules, signalling of metabolic pathways that are unique to the malignant cells. This has the potential to spare the normal cells, thereby reducing toxicity and improving quality of life while continuing to have greater efficacy. Types of targeted therapy: Depending on the mode of action and the specific targets, various agents can be classified in sub-categories. Some of the important ones are Monoclonal antibodies, Tyrosine Kinase Inhibitors, Proteasome inhibitors, Cyclin-Dependent Kinase (CDK) Inhibitors, Raf Kinase Inhibitors, Antiangiogenic agents, Matrix Metalloproteinase Inhibitors Farnesyltransferase Inhibitors, Protein Kinase C Inhibitors, Glutathion-S-transferase Inhibitors, Histone Deacetylase Inhibitors, Cox-2 inhibitors, Antisense Technology and Gene Therapy. Important targeted therapy molecules which are currently approved for human use are listed in Table 1. Table 1 Important targeted therapy drugs approved for human use thead th align=”left” rowspan=”1″ colspan=”1″ Name /th th align=”left” rowspan=”1″ colspan=”1″ Target /th th align=”left” rowspan=”1″ colspan=”1″ Indication /th /thead RituximabCD20Non-Hodgkin lymphomaTrastuzumabHER/neuBreast cancerGemtuzumab ozogamicinCD33Acute myeloid leukemiaAlemtuzumabCD52Chronic lymphocytic leukemiaIbritumomab tiuxetanCD20Non-Hodgkin lymphomaBevacizumabVEGFColorectal cancerBortezomibProteasomeMultiple myelomaCetuximabEGF receptorColorectal cancerGefitinibTyrosine kinaseNon small cell lung cancerImatinibTyrosine kinaseChronic myeloid leukemiaTositumomabCD20Non-Hodgkin lymphomaSorafenibSerine/threonine and receptor tyrosine kinasesAdvanced renal cell carcinomaSunitinib maleateMultiple kinases receptorsGastrointestinal stromal tumour, advanced renal cell carcinoma Open in a separate window According to their mechanism of action, targeted therapy molecules can be classified into following categories: 1. Monoclonal antibodies: It was G. Kohler and C. Milstein [1] in 1975 who developed the hybridoma technology which provides monoclonal antibodies SBI-425 (MAbs) capable of highly specific associations with their target antigens. They produce hybrid cell lines by fusing antibody-producing cells from immunized mice with antibody-secreting mouse cells derived from myeloma and spleen cells. These hybrid cell lines can be cloned and cultured indefinitely. Because of this technology it was possible to produce large amount of individual antibodies. In 1984, both scientists were honoured with the Nobel Prize for their work. MAbs were instantly applicable in diagnosis. However therapeutic use was fought with problems. When these antibodies, produce in mice cell lines, were injected in human they were quickly recognized as foreign proteins and rejected by auto-antibodies, some times even causing serious allergic reactions. It took time for such problems to be tackled. Now it is possible to produce chimeric and humanized mAbs that are therapeutically effective. MAbs mediate their action via variety of mechanisms, and some pathways that are still poorly understood. Some of the known mechanisms include Antibody dependent cellular cytotoxicity (ADCC), Complement-dependent cytotoxicity(CDC), Signal transduction changes, Immunomodulation [2,3] and delivery of cytotoxic payloads (as transport vehicle for other agents) [4]. 2. Tyrosine Kinase Inhibitors: Tyrosine kinases are group of enzymes which are responsible for cellular proliferation, survival, differentiation, function, and motility. After successful invention of imatinib, these are considered as excellent targets for the development of anti cancer therapy. Some of the clinically important types of tyrosine kinases are epidermal growth factor receptor, platelet derived growth factor receptor, vascular endothelial growth factor receptor, and cytosolic Abelson tyrosine kinase. Examples-Imatinib Mesylate (STI571), Gefitinib (ZD1839), Erlotinib (OSI-774), CI-1033, EKB-569, etc. 3. Proteasome inhibitors: Proteasome is an enzyme complex that is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the regulation SBI-425 of apoptosis. Bortezomib is the most important proteosome inhibitor, which is used for the treatment of multiple myeloma. Trials are undergoing for its possible role in leukemia, Waldenstrom Macroglobulinemia, malignant lymphoma, and several solid tumour types. Example C bortezomib (Velcade). 4. Cyclin-Dependent Kinase (CDK) Inhibitors: CDK inhibitors are.Advances in understanding the biology of cancer cells and their metabolic functioning have led to the recognition of several molecule and processes that are unique to the cancerous cells. SBI-425 have been (successfully in several instances) explored as potential targets for cancer directed therapy. This gave birth to the era of targeted therapy. Targeted therapy is defined as a drug or molecule causing tumour cell kill by interacting with predefined target(s) present on malignant cells. Such an approach has obvious advantages. The most important being that it would selectively attack the cell surface molecules, signalling of metabolic pathways that are unique to the malignant cells. This has the potential to spare the normal cells, thereby reducing toxicity and improving quality of life while continuing to have greater efficacy. Types of targeted therapy: Depending on the mode of action and the specific targets, various agents can be classified in sub-categories. Some of the important ones are Monoclonal antibodies, Tyrosine Kinase Inhibitors, Proteasome inhibitors, Cyclin-Dependent Kinase (CDK) Inhibitors, Raf Kinase Inhibitors, Antiangiogenic agents, Matrix Metalloproteinase Inhibitors Farnesyltransferase Inhibitors, Protein Kinase C Inhibitors, Glutathion-S-transferase Inhibitors, Histone Deacetylase Inhibitors, Cox-2 inhibitors, Antisense Technology and Gene Therapy. Important targeted therapy molecules which are currently approved for human use are listed in Table 1. Table 1 Important targeted therapy drugs approved for human use thead th align=”left” rowspan=”1″ colspan=”1″ Name /th th align=”left” rowspan=”1″ colspan=”1″ Target /th th align=”left” rowspan=”1″ colspan=”1″ Indication /th /thead RituximabCD20Non-Hodgkin lymphomaTrastuzumabHER/neuBreast cancerGemtuzumab ozogamicinCD33Acute myeloid leukemiaAlemtuzumabCD52Chronic lymphocytic leukemiaIbritumomab tiuxetanCD20Non-Hodgkin lymphomaBevacizumabVEGFColorectal cancerBortezomibProteasomeMultiple myelomaCetuximabEGF receptorColorectal cancerGefitinibTyrosine kinaseNon small cell lung cancerImatinibTyrosine kinaseChronic myeloid leukemiaTositumomabCD20Non-Hodgkin lymphomaSorafenibSerine/threonine and receptor tyrosine kinasesAdvanced renal cell carcinomaSunitinib maleateMultiple kinases receptorsGastrointestinal stromal tumour, advanced renal cell carcinoma Open in a separate window According to their mechanism of action, targeted therapy molecules can be classified into following categories: 1. Monoclonal antibodies: It was G. Kohler and C. Milstein [1] in 1975 who developed the hybridoma technology which provides monoclonal antibodies (MAbs) capable of highly specific associations with their target antigens. They produce hybrid cell lines by fusing antibody-producing cells from immunized mice with antibody-secreting mouse cells derived from myeloma and spleen cells. These hybrid cell lines can SBI-425 be cloned and cultured indefinitely. Because of this technology it was possible to produce large amount of individual antibodies. In 1984, both scientists were honoured with the Nobel Prize for their work. MAbs were instantly applicable in diagnosis. However therapeutic use was fought with problems. When these antibodies, produce in mice cell lines, were injected in human they were quickly recognized as foreign proteins and rejected by auto-antibodies, some times even causing serious allergic reactions. It took time for such problems to be tackled. Now it is possible to produce chimeric and humanized mAbs that are therapeutically effective. MAbs mediate their action via variety of mechanisms, and some pathways that are still poorly understood. Some of the known mechanisms include Antibody dependent cellular cytotoxicity (ADCC), Complement-dependent cytotoxicity(CDC), Signal transduction changes, Immunomodulation [2,3] and delivery of cytotoxic payloads (as transport vehicle for other agents) [4]. 2. Tyrosine Kinase Inhibitors: Tyrosine kinases are group of enzymes which are responsible for cellular proliferation, survival, differentiation, function, and motility. After successful invention of imatinib, these are considered as excellent targets for the development of anti cancer therapy. Some of the clinically important types of tyrosine kinases are epidermal growth element receptor, platelet derived growth element receptor, vascular endothelial growth element receptor, and cytosolic Abelson tyrosine kinase. Examples-Imatinib Mesylate (STI571), Gefitinib (ZD1839), Erlotinib (OSI-774), CI-1033, EKB-569, etc. 3. Proteasome inhibitors: Proteasome is an enzyme complex that is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the rules of apoptosis. Bortezomib is the most important proteosome inhibitor, which is used for the treatment of multiple myeloma. Tests are undergoing for its possible part in leukemia, Waldenstrom Macroglobulinemia, malignant lymphoma, and several solid tumour types. Example C bortezomib (Velcade). 4. Cyclin-Dependent Kinase (CDK) Inhibitors: CDK inhibitors are SBI-425 able to create cell cycle arrest and induce apoptosis. Example- flavopiridol (HMR1275) is found to be active in colon cancers, NSCLC and ovarian malignancy either as a single agent or in combination with chemotherapeutic providers. 5. Raf Kinase Inhibitors: Rabbit Polyclonal to OR1L8 Raf kinase inhibitors interfere with mechanism of production of Ras. Example-Sorafenib (BAY 43-9006) found out to be effective in renal cell carcinoma 6. Antiangiogenic providers: In the beginning tumour growth depends upon its sponsor for its blood supply..