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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Research Articles

Analysis of Food and Drug Administration–Approved Anticancer Agents in the NCI60 Panel of Human Tumor Cell Lines

Susan L. Holbeck, Jerry M. Collins and James H. Doroshow
Susan L. Holbeck
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Jerry M. Collins
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James H. Doroshow
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DOI: 10.1158/1535-7163.MCT-10-0106 Published May 2010
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  • Figure 1.
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    Figure 1.

    Dose-response graphs for dasatinib assayed in the melanoma panel, showing end point calculations. Dasatinib (NSC 732517) was tested at five concentrations (1 log dilutions from 10−4 mol/L to 10−8 mol/L). Growth percent of 100 corresponds to growth seen in untreated cells. Growth percent of 0 indicates no net growth over the course of the assay (i.e., equal to the number of cells at time zero). Growth percent of -100 results when all cells are killed. Three end points are routinely calculated: (a) GI50, the log mol/L concentration yielding a growth percent of 50 (i.e., 50% growth inhibition); (b) TGI, or total growth inhibition, the log mol/L concentration yielding a growth percent of 0; and (c) LC50, the log mol/L concentration yielding a growth percent of -50, or lethality in 50% of the starting cells. These end points are illustrated for cell line LOX-IMVI (red open circle). Other cell lines displayed are Malme-3M (red open diamond), M14 (red open triangle), MDA-MB-435 (red open square), SK-MEL-2 (solid blue circle), SK-MEL-28 (solid blue diamond), SK-MEL-5 (solid blue triangle), UACC-257 (solid blue square), and UACC-62 (open green circle).

  • Figure 2.
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    Figure 2.

    Clustering of correlations of NCI60 GI50 patterns for all drugs. Pearson correlation coefficients comparing the GI50 patterns of each drug with all other drugs were hierarchically clustered. The agents are color-coded according to mechanistic category: Purple, signaling agents; blue, alkylating and other DNA damaging agents; turquoise, tubulin binders; orange, topoisomerase poisons; green, antimetabolites and nucleosides; red, hormonal agents; gray, all others. The correlation underlying this clustering can be found in Supplementary Table S1, presented in the same sort order as this figure.

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    Figure 3.

    Dose response graphs for all cell lines in the NCI60 panel exposed to imatinib (NSC 743414). Imatinib was tested at five concentrations (1 log dilutions from 10−4 mol/L to 10−8 mol/L). Note that only one of the cell lines, K-562, which harbors a BCR-Abl gene fusion, has significant sensitivity to this BCR-Abl/KIT/PDGFR inhibitor. The GI50 and TGI concentrations for K-562 are indicated. Imatinib did not cause sufficient lethality in this cell line to calculate LC50. The graph is color-coded by tissue of origin: red, leukemia cell line; blue, lung cancer; green, colon cancer; gray, central nervous system cancer; coral, melanoma; purple, ovarian cancer; gold, renal cancer; turquoise, prostate cancer; pink, breast cancer.

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    Figure 4.

    NCI60 graphs for bortezomib (NSC 681239). The data for bortezomib tested at five concentrations (1 log dilutions from 10−6 mol/L to 10−10 mol/L) are presented in two different formats. A, “waterfall” plot of GI50 molar values, with the most sensitive cell lines for each end point at the top of the graph. B, dose-response curves for all cell lines overlaid on the same plot. Cell lines are color-coded as for Fig. 3.

  • Figure 5.
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    Figure 5.

    Clustering of correlations of NCI60 GI50 patterns for the signaling drugs. PCCs for the agents targeting signal transduction were hierarchically clustered in two symmetric dimensions. A heat map of the PCCs is shown, with higher correlations in red and lower PCCs in blue.

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    Figure 6.

    Mean graph plots of GI50 values for gefitinib (NSC 715055) and lapatinib (NSC 745750). GI50 values for each cell line were calculated from dose-response curves. The mean GI50 for each compound across all 60 cell lines was calculated. The difference between the GI50 for a particular cell line and the mean GI50 is plotted. Cell lines that were more sensitive are displayed as bars that project to the right of the mean. Cell lines that were less sensitive are displayed with bars projected to the left. Cell lines are color-coded as in Fig. 3. Mean graphs for two compounds with similar mechanisms are shown. Both gefitinib and lapatinib inhibit the tyrosine kinase EGFR, and lapatinib also inhibits the related kinase ERBB2. The two compounds give similar mean graph patterns. The degree of similarity was quantitated using the COMPARE algorithm, which gave a PCC of 0.88, confirming that these patterns are very similar. The most responsive cell lines to these agents are all wild type for KRAS, in line with what has been observed in the clinic.

Tables

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  • Table 1.

    US Food and Drug Administration–approved anticancer agents: activity in the NCI60 panel

    NameNSC no.Potency in μmol/L
    Mean GI50Mean TGIMean LC50
    Signaling agents
        Bortezomib6812390.000510.00633.6
        Dasatinib7325170.338.951
        Erlotinib7187815.559>90
        Everolimus7335040.0951456
        Gefitinib7150553.21949
        Imatinib743414154381
        Lapatinib7457502.92061
        Nilotinib7475992.91349
        Sorafenib7479711.9630
        Sunitinib7506902.29.631
        Temsirolimus6838640.03851>100
    DNA damaging agents
        Actinomycin D30530.00140.0580.52
        BCNU (Carmustine)40996265170330
        Bendamustine13878360>100>100
        Bleomycin1250661.31223
        Busulfan750210970>1,000
        Carboplatin241240100>220>240
        CCNU (Lomustine)7903736120310
        Chlorambucil308852260580
        Cisplatin1198751.432>420
        Cyclophosphamide26271210>250>250
        Dacarbazine4538855>800>1,000
        Hexamethylmelamine13875140>150>150
        Ifosfamide109724320>440>475
        Melphalan880627110210
        Methoxsalen4592396>100>100
        Mitomycin C269800.716.618
        Mithramycin245590.0130.65200
        Nitrogen mustard7622.819100
        Oxaliplatin2660462.852>90
        Pipobroman2515464210370
        Procarbazine77213440>470>500
        Quinacrine142291.75.219
        Streptozotocin85998570>650>700
        Temozolomide36285697>100>100
        ThioTEPA639670400770
        Triethylenemelamine97068.73375
        Uracil mustard3446224160>410
    Tubulin-directed agents
        Docetaxel6285030.01412>85
        Ixabepilone747973<0.00001<0.00001<0.00001
        Paclitaxel1259730.0253.975
        Vinblastine498420.000010.2832
        Vincristine675740.004513250
        Vinorelbine6082100.0184.252
    Anthracyclines/Topoisomerase poisons
        Daunorubicin821510.0681.110
        Doxorubicin1231270.0972.113
        Epirubicin2569420.22.727
        Etoposide1415406.650420
        Idarubicin2564390.0380.253.8
        Irinotecan6163481458>100
        Mitoxantrone3017390.0590.887.8
        Teniposide1228190.414.620
        Topotecan6096990.0312.543
        Valrubicin2461310.49641
    Antimetabolites/Nucleosides
        5-azacytidine1028160.958.7350
        5-fluorouracil19893181,600>2,400
        6-Mercaptopurine7557.4540>740
        Allopurinol13904304,200>5,000
        Calcium leucovorin359093>100>100
        Capecitabine71280780>10,000>10,000
        Cladribine1050145.155>100
        Clofarabine6068690.422586
        Cytarabine638788.2340>500
        Decitabine12771637260350
        Floxuridine276400.39755>2,400
        Fludarabine31288743410>1,100
        Gemcitabine6133270.241878
        Hydroxyurea32065560>2,000>2,400
        Methotrexate7400.3210>250
        Nelarabine6866732,700>5,000>5,000
        Pemetrexed69803711>100>100
        Pentostatin218321440>480>500
        Thioguanine7521.347210
    Hormonal agents
        Anastrozole7193442,500>9,000>10,000
        Delta-1-testololactone23759420>500>500
        Dimethyltestosterone8853627>80>100
        Dromostanolone propionate121982986>100
        Estramustine7022944285>100
        Ethinyl estradiol109732578>100
        Exemestane7135632568>100
        Fulvestrant71927662>100>100
        Letrozole7193453,400>5,000>5,000
        Megestrol acetate7142364>100>100
        Mitotane38721143773
        Naldrolone23162184583
        Raloxifene7479748.12871
        Tamoxifen1809734.61823
        Toremifene613680132959
    Other
        Amifostine296961540>700>750
        Aminolevulinic acid18509>100>100>100
        Arsenic trioxide7063634.5>10>13
        Celecoxib719627173463
        Dexrazoxane169780160970>2,000
        Imiquimod36910043>100>100
        Lenalidomide747972>100>100>100
        Levamisole177023>100>100>100
        Mesna11389198>100>100
        Nelfinavir7471675.22068
        Romidepsin6301760.000250.00810.038
        Thalidomide66847>100>100>100
        Tretinoin (ATRA)1227585178>100
        Vorinostat7018520.941770
        Zoledronic acid72151764>100>100

    Additional Files

    • Figures
    • Tables
    • Supplementary Data, Holbeck et al.

      Files in this Data Supplement:

      • Supplementary Table 1
      • Supplementary Table 2
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    Molecular Cancer Therapeutics: 9 (5)
    May 2010
    Volume 9, Issue 5
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    Analysis of Food and Drug Administration–Approved Anticancer Agents in the NCI60 Panel of Human Tumor Cell Lines
    Susan L. Holbeck, Jerry M. Collins and James H. Doroshow
    Mol Cancer Ther May 1 2010 (9) (5) 1451-1460; DOI: 10.1158/1535-7163.MCT-10-0106

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    Analysis of Food and Drug Administration–Approved Anticancer Agents in the NCI60 Panel of Human Tumor Cell Lines
    Susan L. Holbeck, Jerry M. Collins and James H. Doroshow
    Mol Cancer Ther May 1 2010 (9) (5) 1451-1460; DOI: 10.1158/1535-7163.MCT-10-0106
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