Significant changes in the treatment of cancer are in the offing. Biotechnological breakthroughs are leading up to a new generation of anticancer therapies, led by the monoclonal antibodies such as trastuzumab. Some of the new approaches to cancer therapy include:
The monoclonal antibodies are antibodies that recognize tumour-specific antigens. Thus they act as “magic bullets” which attack tumour cells, sparing the normal body cells. Hence they provide efficacy without the side effects commonly associated with anticancer drugs. Trastuzumab and rituximab are the first of these treatments to become available, and trastuzumab alone would have touched a quarter of a billion dollars in sales in the year 2000. Monoclonal antibodies can also be conjugated with antitumour drugs, toxins, or radionuclides. In such a situation, the monoclonal antibody may only be used to target the tumor, while the chemotherapeutic agent or radioactive compound does the real damage to the tumour cells. An example of such a treatment is pemtumumab, a potential agent for treating ovarian cancer.
Gene therapy involves modification of the genetic code of the cell, causing a reprogramming of the cell. In cancer, gene therapy may be employed to arrest or prevent the disease. For example, delivering tumour-supressing genes to leukemic cells could stop or reverse the malignant process. Permanent reprogramming will occur if the DNA coding is incorporated into the cells’ genetic apparatus. A virus may be used as a vector to carry the DNA code to the target cells. Incidentally, the majority of gene therapy trials in progress today are targeting cancer and products based on gene therapy are expected to be available in a few years.
Antisense therapy is one approach to regulating gene expression in cancer cells, aiming to “turn off” the genes that cause cancer. It is based on the use of short spans of DNA or RNA to disrupt the expression of disease-related genetic code. Antisense DNA binds to RNA from disease genes, preventing its expression as disease.
Genes may also be introduced into tumor cells to augment cellular function at the tumor site, helping the body to overcome immune tolerance, and to elicit an anti-tumor immune response. The approaches to such transgenic immunotherapy include tumour vaccines and adoptive immunotherapy.
Tumour vaccines involve transfecting genes into tumour cells to render the tumour more immunogenic. This promotes recognition by cytotoxic T lymphocytes and their activation, resulting in an anti-tumour response. A vaccine for tumours initiated or promoted by viruses could be derived from inactivated viruses or from viral antigens.
Cytotoxic T lymphocytes and macrophages from a surgically-excised tumor can proliferate in the presence of interleukin-2 and can then be used for systemic adoptive immunotherapy when injected back into the patient. Administration of such cells can localize tumor sites by stimulating a population of lymphocytes that can lyse tumor cells but not normal cells.
Haemopoietic growth factors
Haemopoietic growth factors are involved in the production of blood cells from the bone marrow and are useful in reducing bone marrow toxicity associated with anticancer agents. These growth factors are cytokines that promote proliferation and differentiation of granulocytes and monocyte/macrophages.They include erythropoietin, granulocyte-macrophage stimulating factor (GM-CSF) and granulocyte stimulating factor (G-CSF). GM-CSF and G-CSF increase the neutrophil count in peripheral blood after high dose chemotherapy followed by bone-marrow transplantation, thus resulting in lesser chances of infections. Erythropoietin can help to replenish red blood cells in aplastic anemia and after cancer chemotherapy. Recently thrombopoietin has been described; this agent may alleviate thrombocytopenia due to inadequate marrow production.
The interferons were originally discovered as natural anti-viral compounds. They are of three types: alpha, beta and gamma. Alpha-interferon, which is produced by leukocytes and lymphoblastoid cells stimulated by viruses and certain microbial cell components, is used clinically for its anticancer activity. The antitumour effects are a result of direct cytotoxicity to tumour cells and stimulation of natural killer cells and macrophages. Alpha-interferon is active in a wide range of malignant disorders, most especially in the treatment of hairy cell leukaemia. Its role in the treatment of other neoplasms is under evaluation.
Interleukin-2 is a natural modulator of the immune system that stimulates specialised immune system cells, namely cytotoxic T-lymphocytes and natural killer cells. Recombinant interleukin-2 is manufactured through DNA technology and administered to the patient by intravenous infusion. Activated lymphocytes will target and kill the cancer cells.
Proeolytic enzyme inhibition
If a growth is confined to its original tissue boundaries, even the rapid cellular multiplication occurring in its early phase may not cause serious disease. However, migration from the original tissue compartment, invasion of normal surrounding tissue and dissemination throughout the body constitute malignancy. To invade and metastasise, tumours release proteolytic enzymes which break down extracellular barriers comprising of a network of components such as laminin, fibronectin and other glycoproteins, collagens, and proteoglycans. Proteolytic enzymes inhibitors could block such break down and play a role in controlling the spread of cancer. One such inhibitor, batimistat, is now under evaluation.
Angiogenesis refers to the formation of new blood vessels. A cancer needs new blood vessels for its growth, and a drug that blocks the formation of these new blood vessels could cut off the tumour’s blood supply, thus destroying it. Many antiangiogenesis agents are being studied, including vascular endothelial growth factor, basic fibroblast growth factor, platelet factor 4, thrombospondin-1, angiostatin and endostatin. In the future, angiogenesis inhibitors could be a regular component of anticancer therapy.
The emerging approaches to cancer management suggest that the treatment of cancer is set to undergo radical change. Successful disease managenent could also mean that perhaps soon enough, cancer will not be a dreaded disease anymore.
11 January 2001.
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This article appeared in Pharma Business, February 2, 2001.
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