Tissue culture methods have made gene therapy and stem cell research possible. The ability to transfect cultured cells with DNA gene sequences has allowed us to assign functions to different genes and understand the mechanisms that activate or redress their function. By the 1960s, cell culture technology was well established in cancer research. The time was right for the interaction between cell biology and genetics that gave birth to molecular biology. Without cell culture, gene therapy and the use of stem cells to repopulate damaged organs would be beyond imagination.
The study of Cell Function Analysis tells us that even when the disease is the same type, different patients' tumors respond differently to the same agents. So it doesn't matter if there is a "target" molecule in the cell that the "targeted" drug is going after, if the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial.
Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, the clinical applicaton of these DNA content assays have been shown to correlate only with response and not survival. And due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of Cell Function Analysis. This analysis can actually integrate all the gene expression into one convenient test result.
In obtaining information from gene mutations (DNA content assays) and/or gene expression (RNA content) it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts for cell response, which is only important insofar as it predicts for tumor response and function. In other words, it correlates only with response and not survival, in entirely retrospective (not prospective) studies.
What are the data supporting the use of testing DNA, RNA and Protein expression? Two retrospective studies from two Harvard-affiliated hospitals, showing response, but not survival advantages, with a grand total of twenty six correlations. And a subsequent study, presented in the July 14, 2005 issue of the New England Journal of Medicine from another laboratory that did not show correlations between gene mutations and patient survival (Volume 353:133-144 Number 2).
There is Cell Function Analysis (functional profiling) that shows data indicating a near doubling in the survival of patients with platinum resistant ovarian cancer, striking correlations between platinum activity and patient survival in previously-untreated ovarian cancer, and a comprehensive meta-analysis of scores of studies reporting response and survival correlations in thousands of patients.
Plus a recent study using an angiogenesis assay describing correlations between cell culture assay results and survival in patients with non-small cell lung cancer. These correlations were based on the actual assay results which had been reported, in real time, prospectively to the doctors who had ordered the assay laboratory tests. There were striking correlations between test results and patient survival, not just response.
Not only is cellular profiling a very important predictive test, but it is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity.
Source: Various Bio-Assay Labs
BMJ 2007;334(suppl_1):s18 (6 January), doi:10.1136/bmj.39034.719942.94
http://www.bmj.com/cgi/content/full/334/suppl_1/s18
Hybrid Mode
