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|Targeted therapies for cancer treatment. |
Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena. Italy.
November 2002. Review Article.
Conventional cancer treatments such as cytotoxic chemo-therapy and radiation therapy have been developed based upon the observation that malignant cells divide at a more rapid rate than the normal cells. For example, ionizing radiation induces DNA damage that, upon multiple cell divisions, may lead to errors in transcription and translation resulting in cell death. Similarly, cytotoxic chemotherapy may interrupt microtubule formation that is essential for mitotic events that ultimately affect cell survival . It is without question that conventional therapies have resulted
in significant survival advantages in patients with breast and colon cancer as examples.
Despite the benefits derived from the antitumor activity of conventional cytotoxic therapies, treatment-related toxicity can substantially reduce quality of life in cancer patients. Therapies directed against rapidly dividing cells will result in death of epithelium (such as the lining of the gastrointestinal tract) or may affect ematopoietic progenitors resulting in cytopenias. These side effects not only reduce the quality of life of cancer patients, but also limit dose intensification and ultimately therapeutic antitumor activity.
The advent of molecular biology techniques that enable rapid isolation and analysis of DNA, RNA, and protein has lead to research efforts that focus on tumor biology at the cellular and subcellular levels. Identification of pathways that are unique to cancer cells has lead to development of cancer drug therapeutics that target specific processes essential to tumor cell survival.
Rituxan is a humanized monoclonal antibody that binds to the CD20 antigen present on B cell lymphomas and is currently approved for the treatment of patients with relapsed or refractory low-grade CD20 positive follicular lymphoma.
Recent data suggest that herceptin monotherapy (humanized anti-HER-2/neu herceptin ) may result in a 26% objective response rate as a first-line treatment in patients with metastatic breast carcinoma
that overexpresses HER-2/neu. These encouraging results have led to current studies of herceptin as a first-line agent in combination with chemotherapy or hormonal
therapy, or both, in the adjuvant and neoadjuvant treatment of patients with primary breast cancer.
Gleevec is a tyrosine kinase inhibitor that inhibits abl-specific phosphorylation and is approved for use in select patients with chronic myelogenous leukemia that is refractory to interferon therapy.
Again, in the subset of patients whose GIST was associated with a c-kit mutation,
oral STI571 resulted in dramatic tumor regression in a significant percentage of patients with a tumor histology that previously had been considered refractory. Gleevec is rapidly being evaluated as a first-line therapy in patients with GIST and other tumors that demonstrate activating c-kit mutations.
Despite the promising clinical results from the agents that have been highlighted, there are still significant limitations to the concept of "pathway-specific" targeted therapies.The first limitation is that these agents are only effective in tumor types that are dependent upon the pathways that are being inhibited. It is readily apparent that most solid tumors are the result of numerous genetic mutations, and thus inhibiting a single cellular pathway may not result in significant therapeutic activity. Design of agents that target a number of pathways will possibly increase the therapeutic
effect, but also increase the risk of treatment-related toxicities
( 1 ).
1) Julian A. Kim. Targeted therapies for the treatment of cancer. The American Journal of Surgery 186 (2003) 264-268. Pub Med
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