Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs--a trait known as multidrug resistance--remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.

/pdf/multidrug-resistance-in-cancer-role-of-atp-dependent-1hpqky19xf.pdf

Multidrug resistance in cancer: role of ATP–dependent transporters

The US National Cancer Institute (NCI) 60 human tumour cell line anticancer drug screen (NCI60) was developed in the late 1980s as an in vitro drug-discovery tool intended to supplant the use of transplantable animal tumours in anticancer drug screening. This screening model was rapidly recognized as a rich source of information about the mechanisms of growth inhibition and tumour-cell kill. Recently, its role has changed to that of a service screen supporting the cancer research community. Here I review the development, use and productivity of the screen, highlighting several outcomes that have contributed to advances in cancer chemotherapy.

The NCI60 human tumour cell line anticancer drug screen

During 1985-1990 the U.S. National Cancer Institute (NCI) phased out its murine leukemia P388 anticancer drug screening program and developed as the replacement a new in vitro primary screen based upon a diverse panel of human tumor cell lines. For each substance tested, the screen generates a remarkably reproducible and characteristic profile of differential in vitro cellular sensitivity, or lack thereof, across the 60 different cell lines comprising the panel. Several investigational approaches to display, analysis and interpretation of such profiles and databases, derived from the testing of tens of thousands of substances during the past 4-5 years since the NCI screen became fully operational, have been explored. A variety of useful, practical applications of the in vitro screen have become apparent. As these applications continue to evolve, they are proving to be complementary to diverse other anticancer screening and drug discovery strategies being developed or pursued elsewhere. Reviewed herein are some practical considerations and selected specific examples, particularly illustrating research applications of the NCI screen that may be more broadly applicable to the search for new anticancer drug development leads with novel profiles of antitumor activity and/or mechanisms of action.

Some Practical Considerations and Applications of the National Cancer Institute In Vitro Anticancer Drug Discovery Screen

Since 1990, the National Cancer Institute (NCI) has screened more than 60,000 compounds against a panel of 60 human cancer cell lines. The 50-percent growth-inhibitory concentration (GI50) for any single cell line is simply an index of cytotoxicity or cytostasis, but the patterns of 60 such GI50 values encode unexpectedly rich, detailed information on mechanisms of drug action and drug resistance. Each compound's pattern is like a fingerprint, essentially unique among the many billions of distinguishable possibilities. These activity patterns are being used in conjunction with molecular structural features of the tested agents to explore the NCI's database of more than 460,000 compounds, and they are providing insight into potential target molecules and modulators of activity in the 60 cell lines. For example, the information is being used to search for candidate anticancer drugs that are not dependent on intact p53 suppressor gene function for their activity. It remains to be seen how effective this information-intensive strategy will be at generating new clinically active agents.

https://science.sciencemag.org/content/sci/275/5298/343.full.pdf

An Information-Intensive Approach to the Molecular Pharmacology of Cancer

In the present study, we report the characterization of the p53 tumor suppressor pathway in the 60 cell lines of the National Cancer Institute (NCI) anticancer drug screen, as well as correlations between the integrity of this pathway and the growth-inhibitory potency of 123 anticancer agents in this screen. Assessment of p53 status in these lines was achieved through complete p53 cDNA sequencing, measurement of basal p53 protein levels and functional assessment of ( a ) transcriptional activity of p53 cDNA from each line in a yeast assay, ( b ) γ-ray-induced G 1 phase cell cycle arrest, and ( c ) γ-ray-induced expression of CIP1/WAF1, GADD45 , and MDM2 mRNA. Our investigations revealed that p53 gene mutations were common in the NCI cell screen lines: 39 of 58 cell lines analyzed contained a mutant p53 sequence. cDNA derived from almost all of the mutant p53 cell lines failed to transcriptionally activate a reporter gene in yeast, and the majority of mutant p53 lines studied expressed elevated basal levels of the mutant p53 protein. In contrast to most of the wild-type p53 -containing lines, cells containing mutant p53 sequence were also deficient in γ-ray induction of CIP1/WAF1, GADD45 , and MDM2 mRNA and the ability to arrest in G 1 following γ-irradiation. Taken together, these assessments provided indications of the integrity of the p53 pathway in the 60 cell lines of the NCI cell screen. These individual p53 assessments were subsequently used to probe a database of growth-inhibitory potency for 123 “standard agents,” which included the majority of clinically approved anticancer drugs. These 123 agents have been tested against these lines on multiple occasions, and a proposed mechanism of drug action had previously been assigned to each agent. Our analysis revealed that cells with mutant p53 sequence tended to exhibit less growth inhibition in this screen than the wild-type p53 cell lines when treated with the majority of clinically used anticancer agents: including DNA cross-linking agents, antimetabolites, and topoisomerase I and II inhibitors. Similar correlations were uncovered when we probed this database using most of the other indices of p53 status we assessed in the lines. Interestingly, a class of agents that differed in this respect was the antimitotic agents. Growth-inhibitory activity of these agents tended, in this assay, to be independent of p53 status. Our characterization of the p53 pathway in the NCI cell screen lines should prove useful to researchers investigating fundamental aspects of p53 biology and pharmacology. This information also allows for the large-scale analysis of the more than 60,000 compounds tested against these lines for novel agents that might exploit defective p53 function as a means of preferential toxicity.

https://cancerres.aacrjournals.org/content/canres/57/19/4285.full.pdf

Characterization of the p53 Tumor Suppressor Pathway in Cell Lines of the National Cancer Institute Anticancer Drug Screen and Correlations with the Growth-Inhibitory Potency of 123 Anticancer Agents

Fifty-eight cell lines in the National Cancer Institute drug screen were analyzed for their ability to efflux the fluorescent dye rhodamine 123 as a functional assay for P-glycoprotein (Pgp). Using flow cytometry, the rhodamine fluorescence was measured for each cell line under four incubation conditions, i.e., after accumulation in the presence or absence of the Pgp antagonist cyclosporin A and after efflux in rhodamine-free medium in the presence or absence of cyclosporin A. The results in some cell lines were compatible with Pgp-mediated efflux. There was a significant correlation between mdr-1 expression and rhodamine efflux in the 58 cell lines (r = 0.788, p = 0.0001). Using the rhodamine efflux data as a seed for COMPARE analysis with the cytotoxicity data on > 30,000 compounds in the National Cancer Institute drug screen database, hundreds of compounds with high correlation coefficients were identified. Selected compounds were tested for reversal of cross-resistance in a multidrug-resistant cell line. A high degree of reversibility, up to 10,000-fold, for some of the compounds was noted in the presence of the Pgp antagonist PSC 833. This finding suggested that compounds with predominately Pgp-mediated resistance were being identified. Using these compounds as seeds for COMPARE analysis against a more restricted database of 187 standard agents, a series of standard compounds were repeatedly identified as having high correlation coefficients with the newly identified Pgp substrates. These standard agents, including phyllanthoside, bisantrene, and homoharringtonine, constitute an mdr-1 profile. New agents identified as being highly correlated with these compounds may benefit from clinical trials with Pgp antagonists.

Rhodamine efflux patterns predict p-glycoprotein substrates in the national cancer institute drug screen

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Rhodamine efflux patterns predict p-glycoprotein substrates in the national cancer institute drug screen