The role of gene amplification in clinical resistance to chemotherapy: a review.
The sometimes disfiguring results of surgical treatment and the occasional undetected dissemination upon presentation may make it desirable to treat squamous cell carcinomas of the head and neck with chemotherapy, either adjunctive or primary. The lack of success of this treatment against this class of tumor indicates a need for better chemotherapeutic agents before it can be used as a primary treatment. To this end, it is important to better understand the mechanisms by which tumor cells can acquire resistance. One clinically important, but poorly understood, mechanism is the acquisition, by a cell, of multiple copies of a gene. Gene amplification can lead to overproduction of a protein which may be a drug target which in turn allows the target to outnumber the drug, or production of an enzyme or carrier which directly reduces the toxicity of a drug. Amplification is likely initiated through the random formation of a non-chromosomal fragment of DNA, or episome, containing the gene of interest. Several proposed mechanisms of formation of episomes involve a recombination, or cross-over, event between adjacent strands of DNA, accompanied by a loss of a circular piece of DNA, the episome. Work to delineate these mechanisms is focusing on the functions and levels of particular proteins and DNA sequences in cells in which resistance occurs at a high frequency, currently being developed in cultured lines of head and neck squamous carcinomas.
Ferguson
P J
PJ
Department of Otolaryngology, St. Joseph's Health Centre, University of Western Ontario, London.
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics*; D004351:Drug Resistance; D005784:Gene Amplification; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D009857:Oncogenes / Q000235:genetics*