Identification of non-cross-resistant platinum compounds with novel cytotoxicity profiles using the NCI anticancer drug screen and clustered image map visualizations
Introduction
Cisplatin, discovered in 1969 by Rosenberg, was introduced into clinical oncology in 1978 and was quickly shown to have activity in a wide range of diseases, most notably testicular and ovarian cancers [1], [2], [3], [4], [5], [6]. Subsequent studies demonstrated activity against lung cancers and cancers of the head and neck, among others [7], [8]. Carboplatin was then introduced as a less toxic platinum analogue [9]. Although clinical studies have not convincingly demonstrated superiority of carboplatin in terms of activity, its toxicity profile has proved an attractive attribute. More recently, oxaliplatin, a member of the diaminocyclohexane (DACH) family of platinum compounds, has gained widespread use in the treatment of colon cancer, a disease in which cisplatin had been considered ineffective. These clinical differences provide evidence of the diversity of drug activities that can be obtained with compounds based on a single structural theme, in this case a single type of metal [10], [11], [12], [13], [14]. Promising platinum compounds still under development include the orally active satraplatin (JM-216), the sterically hindered AMD-473, and BBR3464, a polynuclear platinum with unusual DNA-binding characteristics [15], [16], [17], [18], [19], [20], [21].
Despite some disappointments, the search for novel intravenously administered platinum compounds continues, as does the search for orally active analogues. We previously reported studies in which we used the COMPARE algorithm to analyze activity profiles of platinum compounds in the 60 diverse human cancer cell lines of the National Cancer Institute's anticancer drug screen database [22]. Those analyses focused on cisplatin, carboplatin, tetraplatin and oxaliplatin. When the cytotoxicity profile of cisplatin was compared with that of over 40,000 other compounds in the database, the highest correlations were obtained with other diamino-substituted platinum agents, including carboplatin, and with alkylating agents such as melphalan. In contrast, when the cytotoxicity profile of oxaliplatin, a DACH platinum compound, was used as the seed in COMPARE, the highest correlations were seen with other DACH platinums, including tetraplatin. Consistent with those observations, cell lines selected for cisplatin resistance by chronic exposure to the drug were highly cross-resistant to other diamino-substituted platinums and to melphalan but showed much lower levels of cross-resistance to oxaliplatin and tetraplatin.
Guided by those observations, we set out in the present study to examine the activity patterns of a large number of platinum compounds tested in the screen. Our ultimate goal was to identify newer compounds with novel activity profiles. Whereas our previous studies used the COMPARE algorithm to query the entire screen database using specific platinum compounds as seeds, in the present study we used multiple types of data analysis and visualization, including prominently the clustered image map [23], [24], [25] to examine activity pattern similarities and differences of large numbers of platinum agents simultaneously. Twelve classes of platinum compounds, based on activity patterns and chemical structures, were identified. We further analyzed four of those classes. Finally, to search for agents that might be clinically active against cancer cells resistant to the commonly used platinum drugs cisplatin and oxaliplatin, we used cell lines selected for resistance to those drugs to test a diverse, representative set of 38 platinum agents from the screening program for cross-resistance.
Section snippets
Materials and methods
The NCI-60 anticancer drug screen: the methodology of the NCI-60 screen has been described in detail elsewhere (see http://www.dtp.nci.nih.gov). Briefly, on day zero, the human tumor cell lines are plated in 96-well microtiter plates in RPMI 1640 medium with 5% fetal calf serum and 2 mM l-glutamine. The next day, the drug (dissolved in DMSO) is added so as to achieve five concentrations at 10-fold intervals (plus a negative control). Usually, the concentration range is from 10−4 down to 10−8 M.
Results
With the goal of identifying platinum compounds novel in their activity profiles that were also active against cisplatin- and oxaliplatin-resistant cells, we began by exploiting the data in the National Cancer Institute's anticancer drug screen database. Initially, we identified 303 platinum-containing compounds submitted to the screen for evaluation. After excluding compounds for which the activity data were considered sub-optimal, 173 remained. These 173 clustered into 12 groups, each
Discussion
With the ultimate goal of identifying platinum agents that have novel activity and cross-resistance profiles, we have evaluated over 300 platinum compounds submitted to the NCI anticancer drug screen. Our aim from the outset was to identify novel platinum-containing compounds that could be considered candidates for clinical development. Specifically, we have sought platinum-containing compounds that differ in their pharmacological characteristics from the clinically used agents cisplatin,
Acknowledgements
The authors acknowledge the wonderful guidance, insight and warm friendship of their colleague, Kenneth D. Paull. His contributions to this and other pharmacological analyses of the NCI anticancer drug screen data cannot be measured. We also thank E.A. Sausville, A. Monks, D.A. Scudiero, M. Boyd, M. Grever, R. Shoemaker, V. Narayanan, J. Johnson, R. Schultz, D. Zaharevitz, S. Holbeck, D.G. Covell, and the many others in the NCI Developmental Therapeutics Program who have contributed to the
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