Personalized Cancer Medicine: From Molecular Diagnostics to Targeted Therapy with Natural Products

Abstract

Personalized cancer medicine aims to develop individualized treatment options adapted to factors relevant for the prognosis of each patient. Molecular biomarkers are required to predict the likelihood of an individual tumor's responsiveness or of toxicity in normal organs and to advise optimized treatments with improved efficacy at reduced side effects for each cancer patient. In the present review, we present a concept, which takes advantage of methods of molecular diagnostics to identify predictive markers at the DNA, mRNA, and protein levels. Markers with prognostic value concerning treatment response and patient survival can then be used as targets to develop optimized drugs. We focus on three examples to illustrate this strategy: (i) chemoselective treatment of tumors with 9p21 deletion by L-alanosine, (ii) treatment of multidrug-resistant P-glycoprotein-expressing tumor cells by non-cross-resistant natural products or by inhibitors of P-glycoprotein to overcome multidrug resistance, and (iii) natural products that inhibit the epidermal growth factor receptor (EGFR) in EGFR-overexpressing tumor cells.

Key words

chemotherapy - comparative genomic hybridization - drug resistance - pharmacogenomics - pharmacognosy - traditional Chinese medicine

References

• 1 Evans W E, Relling M V. Pharmacogenomics: translating functional genomics into rational therapeutics.  Science. 1999;  286 487-491
• 2 Fagerlund T H, Braaten O. No pain relief from codeine? An introduction to pharmacogenomics.  Acta Anaesthesiol Scand. 2001;  45 140-149
• 3 Rothenberg M L, Meropol N J, Poplin E A, van Cutsem E, Wadler S. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel.  J Clin Oncol. 2001;  19 3801-3807
• 4 Sargent D J, Niedzwiecki D, O'Connell M J, Schilsky R L. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer.  N Engl J Med. 2001;  345 144-145
• 5 Salmon S E, Hamburger A W, Soehnlein B, Durie B G, Alberts D S, Moon T E. Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs.  N Engl J Med. 1978;  298 1321-1327
• 6 Volm M, Drings P, Mattern J, Sonka J, Vogt-Moykopf I, Wayss K. Prognostic significance of DNA patterns and resistance-predictive tests in non-small cell lung carcinoma.  Cancer. 1985;  56 1396-1403
• 7 Beck W T, Grogan T M, Willmann C L, Cordon-Cardo C, Parham D M, Kuttesch J F, Andreeff M, Bates S E, Berard C W, Boyett J M, Brophy N A, Broxterman H J, Chan H S, Dalton W S, Dietel M, Fojo A T, Gascoyne R D, Head D, Houghton P J, Srivastava D K, Lehnert M, Leith C P, Paietta E, Pavelic Z P, Weinstein R. Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations.  Cancer Res. 1996;  56 3010-3020
• 8 Beck W T, Grogan T M. Methods to detect P-glycoprotein and implications for other drug resistance-associated proteins.  Leukemia. 1997;  11 1107-1109
• 9 Efferth T. Testing for tumor drug resistance in the age of molecular medicine. A contribution to the debate round-table on phenotypic and genotypic analyses of multidrug resistance (MDR) in clinical hospital practice.  Leukemia. 1997;  13 1627-1629
• 10 Volm M, Mattern J. Resistance mechanisms and their regulation in lung cancer.  Crit Rev Oncog. 1996;  7 227-244
• 11 Cortazar P, Johnson B E. Review of the efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing for patients with cancer.  J Clin Oncol. 1999;  17 1625-1631
• 12 Butler M S. Natural products to drugs: natural product derived compounds in clinical trials.  Nat Prod Rep. 2005;  22 162
• 13 Newman D J, Cragg G M. Natural products as sources of new drugs over the last 25 years.  J Nat Prod. 2007;  70 461-477
• 14 Efferth T. Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin – from bench to bedside.  Planta Med. 2007;  73 299-309
• 15 Efferth T, Fu Y J, Zu Y G, Schwarz G, Konkimalla V S, Wink M. Molecular target-guided tumor therapy with natural products derived from traditional Chinese medicine.  Curr Med Chem. 2007;  14 2024-2032
• 16 Efferth T, Li P C, Konkimalla V S, Kaina B. From traditional Chinese medicine to rational cancer therapy.  Trends Mol Med. 2007;  13 353-361
• 17 Collins I, Workman P. New approaches to molecular cancer therapeutics.  Nat Chem Biol. 2006;  2 689
• 18 Jain K K. Challenges of drug discovery for personalized medicine.  Curr Opin Mol Ther. 2006;  8 487-492
• 19 Daly A K. Individualized drug therapy.  Curr Opin Drug Discov Devel. 2007;  10 29-36
• 20 Fujita K, Sasaki Y. Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy.  Curr Drug Metab. 2007;  8 554-562
• 21 Garman K S, Nevins J R, Potti A. Genomic strategies for personalized cancer therapy.  Hum Mol Genet. 2007;  16 R226-R232
• 22 Sikora K. Personalized medicine for cancer: from molecular signature to therapeutic choice.  Adv Cancer Res. 2007;  96 345-369
• 23 Gunawan B, Huber W, Holtrup M, von Heydebreck A, Efferth T, Poustka A, Ringert R H, Jakse G, Füzesi L. Prognostic impacts of cytogenetic findings in clear cell renal cell carcinoma: gain of 5q31-qter predicts a distinct clinical phenotype with favorable prognosis.  Cancer Res. 2001;  61 7731-7738
• 24 Trent J M. Cytogenetics of human malignant melanoma.  Cancer Metastasis Rev. 1991;  10 103-113
• 25 Darling J L, Warr T J, Ashmore S M, Luxsuwong M, Revesz T. Non-isotopic molecular cytogenetics in neuro-oncology.  Neuropathol Appl Neurobiol. 1997;  23 441-456
• 26 Adeyinka A, Mertens F, Idvall I, Bondeson L, Ingvar C, Heim S, Mitelman F, Pandis N. Cytogenetic findings in invasive breast carcinomas with prognostically favourable histology: a less complex karyotypic pattern?.  Int J Cancer. 1998;  79 361-364
• 27 Skapek S X, Chui C H. Cytogenetics and the biologic basis of sarcomas.  Curr Opin Oncol. 2000;  12 315-322
• 28 Risques R A, Ribas M, Peinado M A. Assessment of cumulated genetic alterations in colorectal cancer.  Histol Histopathol. 2003;  18 1289-1299
• 29 Akervall J. Gene profiling in squamous cell carcinoma of the head and neck.  Cancer Metastasis Rev. 2005;  24 87-94
• 30 Campbell L J. Cytogenetics of lymphomas.  Pathology. 2005;  37 493-507
• 31 Keen-Kim D, Nooraie F, Rao P N. Cytogenetic biomarkers for human cancer.  Front Biosci. 2008;  13 5928-5949
• 32 Panani A D. Cytogenetic and molecular aspects of gastric cancer: clinical implications.  Cancer Lett. 2008;  266 99-115
• 33 Harrison C J. Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia.  Br J Haematol. 2009;  144 147-156
• 34 Efferth T, Verdorfer I, Miyachi H, Sauerbrey A, Drexler H G, Chitambar C R, Haber M, Gebhart E. Genomic imbalances in drug-resistant T-cell acute lymphoblastic CEM leukemia cell lines.  Blood Cells Mol Dis. 2002;  29 1-13
• 35 Gebhart E, Thoma K, Verdorfer I, Drexler H G, Efferth T. Genomic imbalances in T-cell acute lymphoblastic leukemia cell lines.  Int J Oncol. 2002;  21 887-894
• 36 Ramirez T, Thoma K, Taja-Chayeb L, Efferth T, Herrera L A, Halatsch M E, Gebhart E. Specific patterns of DNA copy number gains and losses in eight new glioblastoma multiforme cell lines.  Int J Oncol. 2003;  23 453-460
• 37 Patmore H S, Cawkwell L, Stafford N D, Greenman J. Unraveling the chromosomal aberrations of head and neck squamous cell carcinoma: a review.  Ann Surg Oncol. 2005;  12 831-842
• 38 Liehr T, Ries J, Wolff E, Fiedler W, Dahse R, Ernst G, Steininger H, Koscielny S, Girod S, Gebhart E. Gain of DNA copy number on chromosomes 3q26-qter and 5p14-pter is a frequent finding in head and neck squamous cell carcinomas.  Int J Mol Med. 1998;  2 173-179
• 39 Gebhart E, Ries J, Wiltfang J, Liehr T, Efferth T. Genomic gain of the epidermal factor receptor harbouring band 7p12 is part of a complex pattern of genomic imbalances in oral squamous cell carcinomas.  Arch Med Res. 2004;  34 385-394
• 40 Konkimalla V B, Suhas V L, Chandra N R, Gebhart E, Efferth T. Diagnosis and therapy of oral squamous cell carcinoma.  Expert Rev Anticancer Ther. 2007;  7 317-329
• 41 Yan P S, Efferth T, Chen H L, Lin J, Rödel F, Fuzesi L, Huang T H. Use of CpG island microarrays to identify colorectal tumors with a high degree of concurrent methylation.  Methods. 2002;  27 162-169
• 42 Iacopetta B, Kawakami K, Watanabe T. Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup?.  Int J Clin Oncol. 2008;  13 498-503
• 43 Sachidanandam R, Weissman D, Schmidt S C, Kakol J M, Stein L D, Marth G, Sherry S, Mullikin J C, Mortimore B J, Willey D L, Hunt S E, Cole C G, Coggill P C, Rice C M, Ning Z, Rogers J, Bentley D R, Kwok P Y, Mardis E R, Yeh R T, Schultz B, Cook L, Davenport R, Dante M, Fulton L, Hillier L, Waterston R H, McPherson J D, Gilman B, Schaffner S, Van Etten W J, Reich D, Higgins J, Daly M J, Blumenstiel B, Baldwin J, Stange-Thomann N, Zody M C, Linton L, Lander E S, Altshuler D. International SNP Map Working Group . A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms.  Nature. 2001;  409 928-933
• 44 Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease.  Nat Genet. 2003;  33 228-237
• 45 Carlson C S, Eberle M A, Rieder M J, Smith J D, Kruglyak L, Nickerson D A. Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans.  Nat Genet. 2003;  33 518-521
• 46 Risch N. The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches.  Cancer Epidemiol Biomarkers Prev. 2001;  10 733-741
• 47 Efferth T. The human ATP-binding cassette transporter genes: from the bench to the bedside.  Curr Mol Med. 2001;  1 45-65
• 48 Gottesman M M, Fojo T, Bates S E. Multidrug resistance in cancer: role of ATP-dependent transporters.  Nat Rev Cancer. 2002;  2 48-58
• 49 Gillet J P, Efferth T, Remacle J. Chemotherapy induced resistance by ATP-binding cassette transporter genes.  Biochem Biophys Acta. 2007;  1775 237-262
• 50 Efferth T, Osieka R. Clinical relevance of the MDR-1 gene and its gene product, P-glycoprotein, for cancer chemotherapy: a meta-analysis.  Tumor Diagn Ther. 1993;  14 238-243
• 51 Sauerbrey A, Zintl F, Volm M. P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia.  Br J Cancer. 1994;  70 1144-1149
• 52 Volm M, Mattern J, Stammler G, Royer-Pokora B, Schneider S, Weirich A, Ludwig R. Expression of resistance-related proteins in nephroblastoma after chemotherapy.  Int J Cancer. 1995;  63 193-197
• 53 Trock B J, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance.  J Natl Cancer Inst. 1997;  89 917-931
• 54 Marie J P, Legrand O. MDR1/P-GP expression as a prognostic factor in acute leukemias.  Adv Exp Med Biol. 1999;  457 1-9
• 55 Mahadevan D, List A F. Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies.  Blood. 2004;  104 1940-1951
• 56 Hoffmeyer S, Burk O, von Richter O, Arnold H P, Brockmöller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.  Proc Natl Acad Sci USA. 2000;  97 3473-3478
• 57 Ameyaw M M, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N, Folayan G O, Githang'a J, Indalo A, Ofori-Adjei D, Price-Evans D A, McLeod H L. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity.  Pharmacogenetics. 2001;  11 217-221
• 58 Schwab M, Eichelbaum M, Fromm M F. Genetic polymorphism of the human MDR1 drug transporter.  Annu Rev Pharmacol Toxicol. 2003;  43 285-307
• 59 Honda T, Dan Y, Koyabu N, Ieiri I, Otsubo K, Higuchi S, Ohtani H, Sawada Y. Polymorphism of MDR1 gene in healthy Japanese subjects: a novel SNP with an amino acid substitution (Glu108Lys).  Drug Metab Pharmacokinet. 2004;  17 479-481
• 60 Sakaeda T, Nakamura T, Okumura K. Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs.  Pharmacogenomics. 2003;  4 397-410
• 61 Sakaeda T, Nakamura T, Horinouchi M, Kakumoto M, Ohmoto N, Sakai T, Morita Y, Tamura T, Aoyama N, Hirai M, Kasuga M, Okumura K. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects.  Pharm Res. 2001;  18 1400-1404
• 62 Goh B C, Lee S C, Wang L Z, Fan L, Guo J Y, Lamba J, Schuetz E, Lim R, Lim H L, Ong A B, Lee H S. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies.  J Clin Oncol. 2002;  20 3683-3690
• 63 Illmer T, Schuler U S, Thiede C, Schwarz U I, Kim R B, Gotthard S, Freund D, Schäkel U, Ehninger G, Schaich M. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients.  Cancer Res. 2002;  62 4955-4962
• 64 Kim R B. MDR1 single nucleotide polymorphisms: multiplicity of haplotypes and functional consequences.  Pharmacogenetics. 2002;  12 425-427
• 65 Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A, Ohdo S, Ohtani H, Sawada Y, Higuchi S, Otsubo K. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein.  Clin Pharmacol Ther. 2002;  72 209-221
• 66 Efferth T, Sauerbrey A, Steinbach D, Gebhart E, Drexler H G, Miyachi H, Chitambar C R, Becker C M, Zintl F, Humeny A. Analysis of single nucleotide polymorphism C3435T of the multidrug resistance gene MDR1 in acute lymphoblastic leukemia.  Int J Oncol. 2003;  23 509-517
• 67 Humeny A, Rödel F, Rödel C, Sauer R, Füzesi L, Becker C, Efferth T. MDR1 single nucleotide polymorphism C3435T in normal colorectal tissue and colorectal carcinomas detected by MALDI-TOF mass spectrometry.  Anticancer Res. 2003;  23 2735-2740
• 68 Plasschaert S L, Groninger E, Boezen M, Kema I, de Vries E G, Uges D, Veerman A J, Kamps W A, Vellenga E, de Graaf S S, de Bont E S. Influence of functional polymorphisms of the MDR1 gene on vincristine pharmacokinetics in childhood acute lymphoblastic leukemia.  Clin Pharmacol Ther. 2004;  76 220-229
• 69 Gillet J P, Efferth T, Steinbach D, Hamels J, de Longueville F, Bertholet V, Remacle J. Microarray-based detection of multidrug resistance in human tumor cells by expression profiling of ATP-binding cassette transporter genes.  Cancer Res. 2004;  64 8987-8993
• 70 Steinbach D, Gillet J P, Sauerbrey A, Gruhn B, Dawczynski K, Bertholet V, de Longueville F, Zintl F, Remacle J, Efferth T. ABCA3 as a possible cause of drug resistance in childhood acute myeloid leukemia.  Clin Cancer Res. 2006;  12 4357-4363
• 71 Efferth T, Gillet J P, Sauerbrey A, Zintl F, Bertholet V, de Longueville F, Remacle J, Steinbach D. Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia.  Mol Cancer Ther. 2006;  5 1986-1994
• 72 Volm M, Koomägi R, Mattern J, Efferth T. Protein expression profiles indicative for drug resistance of non-small cell lung cancer.  Br J Cancer. 2002;  87 251-257
• 73 Volm M, Koomägi R, Mattern J, Efferth T. Expression profile of genes in non-small cell lung carcinomas from long-term surviving patients.  Clin Cancer Res. 2002;  8 1843-1848
• 74 Volm M, Koomägi R, Mattern J, Efferth T. Protein expression profile of primary human squamous cell lung carcinomas indicative of the incidence of metastases.  Clin Exp Metastasis. 2002;  19 385-390
• 75 Kumar-Sinha C, Chinnaiyan A M. Molecular markers to identify patients at risk for recurrence after primary treatment for prostate cancer.  Urology. 2003;  62 (Suppl. 1) 19-35
• 76 Talwalkar J A, Gores G J. Diagnosis and staging of hepatocellular carcinoma.  Gastroenterology. 2004;  127 (5 Suppl. 1) S126-S132
• 77 Cai Z, Chiu J F, He Q Y. Application of proteomics in the study of tumor metastasis.  Genomics Proteomics Bioinformatics. 2004;  2 152-166
• 78 Everley P A, Zetter B R. Proteomics in tumor progression and metastasis.  Ann NY Acad Sci. 2005;  1059 1-10
• 79 Taylor B S, Varambally S, Chinnaiyan A M. A systems approach to model metastatic progression.  Cancer Res. 2006;  66 5537-5539
• 80 Marguiles A G, Klimberg V S, Bhattacharrya S, Gaddy D, Suva L J. Genomics and proteomics of bone cancer.  Clin Cancer Res. 2006;  12 6217s-6221s
• 81 Pardo M, Dwek R A, Zitzmann N. Proteomics in uveal melanoma research: opportunities and challenges in biomarker discovery.  Expert Rev Proteomics. 2007;  4 273-286
• 82 Mathias R A, Simpson R J. Towards understanding epithelial-mesenchymal transition: a proteomics perspective.  Biochim Biophys Acta. 2009;  1794 1325-1331
• 83 Goodison S, Urquidi V. Breast tumor metastasis: analysis via proteomic profiling.  Expert Rev Proteomics. 2008;  5 457-467
• 84 Efferth T, Rücker G, Falkenberg M, Manns D, Olbrich A, Fabry U, Osieka R. Detection of apoptosis in KG-1a leukemic cells treated with investigational drugs.  Arzneimittelforschung. 1996;  46 196-200
• 85 Konkimalla V B, Efferth T. Evidence-based Chinese medicine for cancer therapy.  J Ethnopharmacol. 2008;  116 207-210
• 86 Efferth T. Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy.  Drug Resist Updat. 2005;  8 85-97
• 87 Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells.  Curr Drug Targets. 2006;  7 407-421
• 88 Efferth T. Microarray-based prediction of cytotoxicity of tumor cells to cantharidin.  Oncol Rep. 2005;  13 459-463
• 89 Efferth T, Kaina B. Microarray-based prediction of cytotoxicity of tumor cells to arsenic trioxide.  Cancer Genomics Proteomics. 2004;  1 363-370
• 90 Efferth T, Oesch F. Oxidative stress response of tumor cells: microarray-based comparison between artemisinins and anthracyclines.  Biochem Pharmacol. 2004;  68 3-10
• 91 Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar C R. The anti-malarial artesunate is also active against cancer.  Int J Oncol. 2001;  18 767-773
• 92 Efferth T, Olbrich A, Sauerbrey A, Ross D D, Gebhart E, Neugebauer M. Activity of ascaridol from the anthelmintic herb Chenopodium anthelminticum L. against sensitive and multidrug-resistant tumor cells.  Anticancer Res. 2002;  22 4221-4224
• 93 Efferth T, Davey M, Olbrich A, Rücker G, Gebhart E, Davey R. Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells.  Blood Cells Mol Dis. 2002;  28 160-168
• 94 Efferth T, Olbrich A, Bauer R. mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether.  Biochem Pharmacol. 2002;  64 617-623
• 95 Efferth T, Sauerbrey A, Halatsch M E, Ross D D, Gebhart E. Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines.  Naunyn Schmiedebergs Arch Pharmacol. 2003;  367 56-67
• 96 Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber H O, Hengstler J G, Halatsch M E, Volm M, Tew K D, Ross D D, Funk J O. Molecular modes of action of artesunate in tumor cell lines.  Mol Pharmacol. 2003;  64 382-394
• 97 Efferth T, Briehl M M, Tome M E. Role of antioxidant genes for the activity of artesunate against tumor cells.  Int J Oncol. 2003;  23 1231-1235
• 98 Efferth T, Benakis A, Romero M R, Tomicic M, Rauh R, Steinbach D, Häfer R, Stamminger T, Oesch F, Kaina B, Marschall M. Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron.  Free Radic Biol Med. 2004;  37 998-1009
• 99 Efferth T, Ramirez T, Gebhart E, Halatsch M E. Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774.  Biochem Pharmacol. 2004;  67 1689-1700
• 100 Efferth T, Chen Z, Kaina B, Wang G. Molecular determinants of response of tumor cells to berberine.  Cancer Genomics Proteomics. 2005;  2 115-124
• 101 Efferth T, Rauh R, Kahl S, Tomicic M, Böchzelt H, Tome M E, Briehl M M, Bauer R, Kaina B. Molecular modes of action of cantharidin in tumor cells.  Biochem Pharmacol. 2005;  69 811-818
• 102 Efferth T, Volm M. Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate.  In Vivo. 2005;  19 225-232
• 103 Dell'Eva R, Pfeffer U, Vene R, Anfosso L, Forlani A, Albini A, Efferth T. Inhibition of angiogenesis in vivo and growth of Kaposi's sarcoma xenograft tumors by the anti-malarial artesunate.  Biochem Pharmacol. 2004;  68 2359-2366
• 104 Rinner B, Siegl V, Pürstner P, Efferth T, Brem B, Greger H, Pfragner R. Activity of novel plant extracts against medullary thyroid carcinoma cells.  Anticancer Res. 2004;  24 495-500
• 105 Berger T G, Dieckmann D, Efferth T, Schultz E S, Funk J O, Baur A, Schuler G. Artesunate in the treatment of metastatic uveal melanoma – first experiences.  Oncol Rep. 2005;  14 1599-1603
• 106 Adams M, Efferth T, Bauer R. Activity-guided isolation of scopoletin and isoscopoletin, the inhibitory active principles towards CCRF-CEM leukaemia cells and multidrug resistant CEM/ADR5000 cells from Artemisia argyi.  Planta Med. 2006;  72 862-864
• 107 Anfosso L, Efferth T, Albini A, Pfeffer U. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins.  Pharmacogenomics J. 2006;  6 269-278
• 108 Fu Y J, Efferth T, Zu Y G. Optimization of luteolin separation from pigeonpea [Cajanus cajan(L.) Millsp.] leaves by macroporous resins.  J Chromatogr A. 2006;  1137 145-152
• 109 Fu Y, Zu Y, Zhang L, Zhang L, Tong M, Efferth T, Kong Y, Hou C, Chen L. Determination of vitexin and isovitexin in pigeonpea using ultrasonic extraction followed by LC-MS.  J Sep Sci. 2008;  31 268-275
• 110 Wang J, Zheng Y, Efferth T, Wang R, Shen Y, Hao X. Indole and carbazole alkaloids from Glycosmis montana with weak anti-HIV and cytotoxic activities.  Phytochemistry. 2005;  66 697-701
• 111 Wang Y F, Cao J X, Efferth T, Lai G F, Luo S D. Cytotoxic and new tetralone derivatives from Berchemia floribunda (Wall.) Brongn.  Chem Biodivers. 2006;  3 646-653
• 112 Wang Y F, Lai G F, Efferth T, Cao J X, Luo S D. New glycosides from Tetracentron sinense and their cytotoxic activity.  Chem Biodivers. 2006;  3 1023-1030
• 113 Efferth T, Marschall M, Wang X, Huong S M, Hauber I, Olbrich A, Kronschnabl M, Stamminger T, Huang E S. Antiviral activity of artesunate towards wild type, recombinant, and ganciclovir-resistant human cytomegaloviruses.  J Mol Med. 2002;  80 233-242
• 114 Kaptein S J, Efferth T, Leis M, Rechter S, Auerochs S, Kalmer M, Bruggeman C A, Vink C, Stamminger T, Marschall M. The anti-malaria drug artesunate inhibits replication of cytomegalovirus in vitro and in vivo.  Antiviral Res. 2006;  69 60-69
• 115 Romero M R, Efferth T, Serrano M A, Castaño B, Macias R I, Briz O, Marin J J. Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an “in vitro” replicative system.  Antiviral Res. 2005;  68 75-83
• 116 Romero M R, Serrano M A, Vallejo M, Efferth T, Alvarez M, Marin J J. Antiviral effect of artemisinin from Artemisia annua against a model member of the Flaviviridae family, the bovine viral diarrhoea virus (BVDV).  Planta Med. 2006;  72 1169-1174
• 117 Volm M, Wagner-Pommerenke E, Efferth T, Löhrke H, Mattern J. Circumvention of multidrug-resistance in human kidney and kidney carcinoma in vitro.  Cancer. 1991;  67 2484-2489
• 118 Cairns P, Polascik T J, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W, Rutter J L, Buckler A, Gabrielson E, Tockman M, Cho K, Hedrick L, Bova G S, Isaacs W, Koch W, Schwab D, Sidransky D. Frequency of homozyous deletion at p 16/CDKN2 in primary human tumours.  Nat Genet. 1995;  11 210-212
• 119 Nobori T, Takabayashi K, Tran P, Orvis L, Batova A, Yu A L, Carson D A. Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers.  Proc Natl Acad Sci USA. 1996;  93 6203-6208
• 120 Sherr C J. The ink4a/arf network in tumour suppression.  Nat Rev Mol Cell Biol. 2001;  2 731-737
• 121 Della Ragione F, Russo G, Oliva A, Mastropietro S, Mancini A, Borrelli A, Casero R A, Iolascon A, Zappia V. 5′-Deoxy-5′-methylthioadenosine phosphorylase and p 16INK4 deficiency in multiple tumor cell lines.  Oncogene. 1995;  10 827-833
• 122 Katamani N, Nelson-Rees W A, Carson D A. Selective killing of human malignant cell lines deficient in methylthioadenosine phosphorylase, a purine metabolic enzyme.  Proc Natl Acad Sci USA. 1981;  78 1219-1223
• 123 Efferth T, Miyachi H, Drexler H G, Gebhart E. Methylthioadenosine phosphorylase as target for chemoselective treatment of T-cell acute lymphoblastic leukemic cells.  Blood Cells Mol Dis. 2002;  28 47-56
• 124 Efferth T, Gebhart E, Ross D D, Sauerbrey A. Identification of gene expression profiles predicting tumor cell response to L-alanosine.  Biochem Pharmacol. 2003;  66 613-621
• 125 Efferth T, Konkimalla V B, Wang Y F, Sauerbrey A, Meinhardt S, Zintl F, Mattern J, Volm M. Prediction of broad spectrum resistance of tumors towards anti-cancer drugs.  Clin Cancer Res. 2008;  14 2405-2412
• 126 Konkimalla V B, Efferth T. Anti-cancer natural product library from traditional Chinese medicine.  Comb Chem High Throughput Screen. 2008;  11 7-15
• 127 Nobilit S, Landini I, Giglioni B, Mini E. Pharmacological strategies for overcoming multidrug resistance.  Curr Drug Targets. 2006;  7 861-879
• 128 Takara K, Sakaeda T, Okumura K. An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy.  Curr Pharm Des. 2006;  12 273-286
• 129 Adams M, Mahringer A, Kunert O, Fricker G, Efferth T, Bauer R. Cytotoxicity and p-glycoprotein modulating effects of quinolones and indoloquinazolines from the Chinese herb Evodia rutaecarpa.  Planta Med. 2007;  73 1554-1557
• 130 Adams M, Mahringer A, Bauer R, Fricker G, Efferth T. In vitro cytotoxicity and P-glycoprotein modulating effects of geranylated furocoumarins from Tetradium daniellii.  Planta Med. 2007;  73 1475-1478
• 131 Majumder S, Dutta P, Mukherjee P, Datta E R, Efferth T, Bhattacharya S, Choudhuri S K. Reversal of drug resistance in P-glycoprotein-expressing T-cell acute lymphoblastic CEM leukemia cells by copper N-(2-hydroxy acetophenone) glycinate and oxalyl bis(N-phenyl)hydroxamic acid.  Cancer Lett. 2006;  244 16-23
• 132 Mookerjee A, Basu J M, Majumder S, Chatterjee S, Panda G S, Dutta P, Pal S, Mukherjee P, Efferth T, Roy S, Choudhuri S K. A novel copper complex induces ROS generation in doxorubicin resistant Ehrlich ascitis carcinoma cells and increases activity of antioxidant enzymes in vital organs in vivo.  BMC Cancer. 2006;  6 267
• 133 Mookerjee A, Mookerjee Basu J, Dutta P, Majumder S, Bhattacharyya S, Biswas J, Pal S, Mukherjee P, Raha S, Baral R N, Das T, Efferth T, Sa G, Roy S, Choudhuri S K. Overcoming drug-resistant cancer by a newly developed copper chelate through host-protective cytokine-mediated apoptosis.  Clin Cancer Res. 2006;  12 4339-4349
• 134 Weiss J, Rose J, Storch C H, Ketabi-Kiyanvash N, Sauer A, Haefeli W E, Efferth T. Modulation of human BCRP (ABCG2) activity by anti-HIV drugs.  J Antimicrob Chemother. 2007;  59 238-245
• 135 Perea S, Hidalgo M. Predictors of sensitivity and resistance to epidermal growth factor receptor inhibitors.  Clin Lung Cancer. 2004;  6 S30-S34
• 136 Lee C S, deFazio A, Ormandy C J, Sutherland R L. Inverse regulation of oestrogen receptor and epidermal growth factor receptor gene expression in MCF-7 breast cancer cells treated with phorbol ester.  J Steroid Biochem Mol Biol. 1996;  58 267-275
• 137 Wood E R, Truesdale A T, McDonald O B, Yuan D, Hassell A, Dickerson S H, Ellis B, Pennisi C, Horne E, Lackey K, Alligood K J, Rusnak D W, Gilmer T M, Shewchuk L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib), relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells.  Cancer Res. 2004;  64 6652-6659
• 138 Bremnes R M, Veve R, Gabrielson E, Hirsch F R, Baron A, Bemis L, Gemmill R M, Drabkin H A, Franklin W A. High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer.  J Clin Oncol. 2002;  20 2417-2428
• 139 Nawrocki S, Skacel T, Brodowicz T. From microarrays to new therapeutic approaches in bladder cancer.  Pharmacogenomics. 2003;  4 179-189
• 140 Rich J N, Hans C, Jones B, Iversen E S, McLendon R E, Rasheed B K, Dobra A, Dressman H K, Bigner D D, Nevins J R, West M. Gene expression profiling and genetic markers in glioblastoma survival.  Cancer Res. 2005;  65 4051-4058
• 141 Crijns A P, Duiker E W, de Jong S, Willemse P H, van der Zee A G, de Vries E G. Molecular prognostic markers in ovarian cancer: toward patient-tailored therapy.  Int J Gynecol Cancer. 2006;  16 (Suppl. 1) 152-165
• 142 Seigneuric R, Starmans M H, Fung G, Krishnapuram B, Nuyten D S, van Erk A, Magagnin M G, Rouschop K M, Krishnan S, Rao R B, Evelo C T, Begg A C, Wouters B G, Lambin P. Impact of supervised gene signatures of early hypoxia on patient survival.  Radiother Oncol. 2007;  83 374-382
• 143 Tan B K, Tan L K, Yu K, Tan P H, Lee M, Sii L H, Wong C Y, Ho G H, Yeo A W, Chow P K, Koong H N, Yong W S, Lim D T, Ooi L L, Soo K C, Tan P. Clinical validation of a customized multiple signature microarray for breast cancer.  Clin Cancer Res. 2008;  14 461-469
• 144 Chanrion M, Negre V, Fontaine H, Salvetat N, Bibeau F, Mac Grogan G, Mauriac L, Katsaros D, Molina F, Theillet C, Darbon J M. A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer.  Clin Cancer Res. 2008;  14 1744-1752
• 145 Wooster R. Cancer classification with DNA microarrays. Is less more?.  Trends Genet. 2000;  16 327-329
• 146 Gillet J P, Schneider J, Bertholet V, de Longueville F, Remacle J, Efferth T. Microarray expression profile of ABC transporters in human breast cancer.  Cancer Genomics Proteomics. 2006;  3 97-106
• 147 Volm M, Efferth T, Mattern J. Oncoprotein (c-myc, c-erbB1, c-erbB2, c-fos) and suppressor gene product (p 53) expression in squamous cell carcinomas of the lung. Clinical and biological correlations.  Anticancer Res. 1992;  12 11-20