Article Figures & Data
Figures
- 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.
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.
- 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.
- 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.
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.
- 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
- Table 1.
US Food and Drug Administration–approved anticancer agents: activity in the NCI60 panel
Name NSC no. Potency in μmol/L Mean GI50 Mean TGI Mean LC50 Signaling agents Bortezomib 681239 0.00051 0.0063 3.6 Dasatinib 732517 0.33 8.9 51 Erlotinib 718781 5.5 59 >90 Everolimus 733504 0.095 14 56 Gefitinib 715055 3.2 19 49 Imatinib 743414 15 43 81 Lapatinib 745750 2.9 20 61 Nilotinib 747599 2.9 13 49 Sorafenib 747971 1.9 6 30 Sunitinib 750690 2.2 9.6 31 Temsirolimus 683864 0.038 51 >100 DNA damaging agents Actinomycin D 3053 0.0014 0.058 0.52 BCNU (Carmustine) 409962 65 170 330 Bendamustine 138783 60 >100 >100 Bleomycin 125066 1.3 12 23 Busulfan 750 210 970 >1,000 Carboplatin 241240 100 >220 >240 CCNU (Lomustine) 79037 36 120 310 Chlorambucil 3088 52 260 580 Cisplatin 119875 1.4 32 >420 Cyclophosphamide 26271 210 >250 >250 Dacarbazine 45388 55 >800 >1,000 Hexamethylmelamine 13875 140 >150 >150 Ifosfamide 109724 320 >440 >475 Melphalan 8806 27 110 210 Methoxsalen 45923 96 >100 >100 Mitomycin C 26980 0.71 6.6 18 Mithramycin 24559 0.013 0.65 200 Nitrogen mustard 762 2.8 19 100 Oxaliplatin 266046 2.8 52 >90 Pipobroman 25154 64 210 370 Procarbazine 77213 440 >470 >500 Quinacrine 14229 1.7 5.2 19 Streptozotocin 85998 570 >650 >700 Temozolomide 362856 97 >100 >100 ThioTEPA 6396 70 400 770 Triethylenemelamine 9706 8.7 33 75 Uracil mustard 34462 24 160 >410 Tubulin-directed agents Docetaxel 628503 0.014 12 >85 Ixabepilone 747973 <0.00001 <0.00001 <0.00001 Paclitaxel 125973 0.025 3.9 75 Vinblastine 49842 0.00001 0.28 32 Vincristine 67574 0.0045 13 250 Vinorelbine 608210 0.018 4.2 52 Anthracyclines/Topoisomerase poisons Daunorubicin 82151 0.068 1.1 10 Doxorubicin 123127 0.097 2.1 13 Epirubicin 256942 0.2 2.7 27 Etoposide 141540 6.6 50 420 Idarubicin 256439 0.038 0.25 3.8 Irinotecan 616348 14 58 >100 Mitoxantrone 301739 0.059 0.88 7.8 Teniposide 122819 0.41 4.6 20 Topotecan 609699 0.031 2.5 43 Valrubicin 246131 0.49 6 41 Antimetabolites/Nucleosides 5-azacytidine 102816 0.95 8.7 350 5-fluorouracil 19893 18 1,600 >2,400 6-Mercaptopurine 755 7.4 540 >740 Allopurinol 1390 430 4,200 >5,000 Calcium leucovorin 3590 93 >100 >100 Capecitabine 712807 80 >10,000 >10,000 Cladribine 105014 5.1 55 >100 Clofarabine 606869 0.42 25 86 Cytarabine 63878 8.2 340 >500 Decitabine 127716 37 260 350 Floxuridine 27640 0.39 755 >2,400 Fludarabine 312887 43 410 >1,100 Gemcitabine 613327 0.24 18 78 Hydroxyurea 32065 560 >2,000 >2,400 Methotrexate 740 0.3 210 >250 Nelarabine 686673 2,700 >5,000 >5,000 Pemetrexed 698037 11 >100 >100 Pentostatin 218321 440 >480 >500 Thioguanine 752 1.3 47 210 Hormonal agents Anastrozole 719344 2,500 >9,000 >10,000 Delta-1-testololactone 23759 420 >500 >500 Dimethyltestosterone 88536 27 >80 >100 Dromostanolone propionate 12198 29 86 >100 Estramustine 702294 42 85 >100 Ethinyl estradiol 10973 25 78 >100 Exemestane 713563 25 68 >100 Fulvestrant 719276 62 >100 >100 Letrozole 719345 3,400 >5,000 >5,000 Megestrol acetate 71423 64 >100 >100 Mitotane 38721 14 37 73 Naldrolone 23162 18 45 83 Raloxifene 747974 8.1 28 71 Tamoxifen 180973 4.6 18 23 Toremifene 613680 13 29 59 Other Amifostine 296961 540 >700 >750 Aminolevulinic acid 18509 >100 >100 >100 Arsenic trioxide 706363 4.5 >10 >13 Celecoxib 719627 17 34 63 Dexrazoxane 169780 160 970 >2,000 Imiquimod 369100 43 >100 >100 Lenalidomide 747972 >100 >100 >100 Levamisole 177023 >100 >100 >100 Mesna 113891 98 >100 >100 Nelfinavir 747167 5.2 20 68 Romidepsin 630176 0.00025 0.0081 0.038 Thalidomide 66847 >100 >100 >100 Tretinoin (ATRA) 122758 51 78 >100 Vorinostat 701852 0.94 17 70 Zoledronic acid 721517 64 >100 >100
Supplementary Data, Holbeck et al.
Files in this Data Supplement:
Volume 9, Issue 5
