Current Status of Cell Culture Drug Resistance Testing (CCDRT)
Cell culture drug resistance tests (CCDRT) are laboratory tests in which fresh biopsy specimens of human tumors are cultured in the presence and absence of anticancer drugs. At the conclusion of the cell culture, measurements are made to determine whether or not the drugs were effective in either killing the tumor cells or in preventing the growth of the tumor cells. Proponents of these tests maintain that this information correlates with drug effects in the patient and can therefore be used to assist the clinical oncologist in selecting the most appropriate drugs to be used in the treatment of individual patients. This paper will review the data relevant to this point of view.
To begin with, there has been an unfortunate proliferation of names/terms applying to this testing. It should be noted that the terms "chemosensitivity assay," "chemoresistance assay," "drug resistance assay," and "drug response assay" can be used interchangeably. Likewise, the terms "in vitro assay" and "ex vivo assay" can be used interchangeably in this context. Some authors have tried to draw a distinction between assays which are geared and/or used more for the identification of inactive drugs versus active drugs. These are, however, purely semantic distinctions. Depending on where cut-off lines are drawn, all assays will have differing specificities and sensitivities for identifying inactive drugs and active drugs. It is much more useful to describe the specificity and sensitivity of an assay than to arbitrarily label the assay to be either a "chemoresistance" or "chemosensitivity" assay. The generic term "cell culture drug resistance testing" (CCDRT) describes laboratory tests in which gradations of drug resistance are determined by measuring drug effects on short term cultures of viable cells. Depending on the conditions of the assays, they will have greater and lesser specificities and sensitivities for identifying inactive drugs and active drugs.
One must begin by understanding that there is a clear divide between CCDRT based on cell proliferation as an endpoint and CCDRT based on cell death as an endpoint. Historically, the cell proliferation endpoint received great attention, as a result of studies by Salmon, Von Hoff, and others during the late 1970s and early 1980s [1,2]. These studies occurred during the heyday of the oncogene discovery period in cancer research, where oncogene products were frequently found to be associated with cell growth, and where cancer was most prominently considered to be a disease of disordered cell growth. In contrast, the concept of apoptosis (programmed cell death) had yet to become widely recognized. Also unrecognized were the concepts that cancer may be a disease of disordered apoptosis/cell death and that the mechanisms of action of most if not all available anticancer drugs may be mediated through apoptosis [3-5]. When problems with proliferation-based assays emerged [6,7], there was little enthusiasm for studying cell death as an alternative endpoint. These factors explain the abandonment of research into CCDRT by American universities and cancer centers by the mid-80s. However, clinical laboratories began to offer CCDRT as a service to patients in the USA by the late 1980s, and studies of CCDRT continued in Europe and Asia.
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