Author:
Gregory D. Pawelski
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Date Posted: 19:59:17 08/28/05 Sun
In reply to:
Gregory D. Pawelski
's message, "Chemosensitivity Testing" on 02:45:52 03/16/04 Tue
Cell Culture Drug Resistance Testing (CCDRT) first began testing gemcitabine plus cisplatin combination in the mid-90's at the specific suggestion of Dr. Robert Nagourney, Director of Rational Therapeutics, Inc.. Before then, it was virutually unexplored and many patients received treatment with this regimen because of the CCDRT results long before any clinical trials in their particular disease types had ever been published. Dr. Nagourney's contributions in terms of recognizing the profound synergy of this combination and promoting the use of this combination have been very important in getting clinical trials with this regimen started in a broad spectrum of cancers.
There was a summary paper from a National Cancer Institute study, presented at the American Society of Clinical Oncologists (ASCO) Annual Conference in 1998, which looked at thirteen different studies that searched into "in vitro" (chemosensitivity assay) drug sensitivity testing for patients with cancer. It was noted that with the many different cancers represented in these studies, chemotherapy response rates went up from 3 to 66% (using standard chemotherapy drugs and procedures) and from 21 to 81% (using "in vitro" testing for the most responsive drug) and patient survival increased from 4.5 to 11.2 months (using standared procedures) and from 6.2 to 38.5 months (using "in vitro" testing).
A prospective, randomized clinical trial of physician's choice chemotherapy versus ATP assay-directed chemotherapy in non-surgically debulked, platinum-resistant ovarian cancer was presented by Ian Cree, M.D., Ph.D., Director, Translational Oncology Research Centre, Portsmouth, England at the May, 2005 ASCO meeting in Orlando, Florida. The results were highly suggestive of an effect due to the assay, and the most successful drug regimens used were nearly all developed using the assay. UK results in cancer are always lower than in the US for a variety of reasons. Part of this is probably lead time bias, but data on surgical debulking may be part of the explanation. Patients in the US get a whole lot more surgery along the way than in Germany and England, and it's not sure that it's our chemo which is doing the job or our surgery.
In 1983, medical publications introduced assays based on "cell-death" (not cell-growth). This was a good five years before understanding the concept of apoptosis (apoptosis is a genetically programmed cell death pathway which exists in all cells, which is supposed to cause them to commit suicide if they become functionally deranged, but doesn't function properly in cancer cells, allowing them to grow abnormally without committing suicide, which can be triggered to occur by effective anti-cancer drugs).
Because clinical oncologists did not understand apoptosis then, these pioneering publications with "cell-death" (instead of cell growth) endpoints were ignored, and neither clinical trials nor the application of cell death drug resistance assays were supported by academic and private practice clinical oncologists. The clinical utility and clinical accuracy of cell culture drug resistance testing with cell-death endpoints has now been proven.
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