Horm Metab Res 2003; 35(11/12): 843-849
DOI: 10.1055/s-2004-814158
Review
© Georg Thieme Verlag Stuttgart · New York

Development of Molecular Agents for IGF Receptor Targeting

A.  J.  Salisbury1 , V.  M.  Macaulay1
  • 1Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS UK
Further Information

Publication History

Received 1 September 2003

Accepted without Revision 21 October 2003

Publication Date:
07 January 2004 (online)

Abstract

The type 1 insulin-like growth factor receptor (IGF1R) is a promising anticancer treatment target, being frequently overexpressed by tumours, and mediating proliferation, motility and apoptosis protection. Design of specific kinase inhibitors is problematic because of homology between the IGF1R and insulin receptor. This obstacle can be circumvented using sequence-specific molecular agents including antisense, triplex and ribozymes. Recent studies indicate that profound sequence-specific IGF1R gene silencing can be induced by small interfering RNAs that mediate RNA interference in mammalian cells. IGF1R downregulation blocks tumour growth and metastasis, and enhances sensitivity to cytotoxic drugs and irradiation. In murine melanoma cells, radiosensitisation is associated with impaired activation of Atm, which is required for initiation of cell cycle checkpoints and DNA repair pathways after double-strand DNA breaks. Furthermore, tumour cells killed in vivo following IGF1R downregulation can provoke an immune response, protecting against tumour rechallenge. After years of studying the role of the IGF system in tumour biology, novel agents for IGF1R targeting will soon be available for clinical testing. This review summarises the development of molecular agents, and considers factors that will influence clinical activity, including the requirement of established tumours for IGF signalling, and the efficacy and toxicity of IGF1R inhibitors.

References

  • 1 Liu J P, Baker J, Perkins A S, Robertson E J, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor-I (IGF-1) and type-1 IGF receptor (IGF1R).  Cell. 1993;  75 59-72
  • 2 Baker J, Liu J P, Robertson E J, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth.  Cell. 1993;  75 73-82
  • 3 Khandwala H M, McCutcheon I E, Flyvbjerg A, Friend K E. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth.  Endocr Rev. 2000;  21 215-244
  • 4 Hakam A, Yeatman T J, Mora L, Marcet G, Nicosia S V, Karl R C, Coppola D. Expression of insulin-like growth factor-1 receptor in human colorectal cancer.  Hum Pathol. 1999;  30 1128-1133
  • 5 Kanter-Lewensohn L, Dricu A, Girnita L, Wejde J, Larsson O. Expression of insulin-like growth factor-1 receptor (IGF-1R) and p27Kip1 in melanocytic tumors: a potential regulatory role of IGF-1 pathway in distribution of p27Kip1 between different cyclins.  Growth Factors. 2000;  17 193-202
  • 6 Bergmann U, Funatomi H, Yokoyama M, Berger H G, Korc M. Insulin-like growth-factor-i overexpression in human pancreatic-cancer - evidence for autocrine and paracrine roles.  Cancer Res. 1995;  55 2007-2011
  • 7 Hellawell G O, Turner G D, Davies D R, Poulsom R, Brewster S F, Macaulay V M. Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease.  Cancer Res. 2002;  62 2942-2950
  • 8 Werner H, Roberts C T Jr. The IGFI receptor gene: a molecular target for disrupted transcription factors.  Genes Chromosomes Cancer. 2003;  36 113-120
  • 9 Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B. The IGF-I receptor in cell growth, transformation and apoptosis.  Biochim Biophys Acta. 1997;  1332 F105-126
  • 10 Bohula E, Playford M, Macaulay V. Targeting the type 1 insulin-like growth factor receptor as anticancer treatment.  Anticancer Drugs. 2003;  14 669-682
  • 11 Dunn S E, Hardman R A, Kari F W, Barrett J C. Insulin-like-growth-factor-1 (IGF-1) alters drug-sensitivity of HBL100 human breast-cancer cells by inhibition of apoptosis induced by diverse anticancer drugs.  Cancer Res. 1997;  57 2687-2693
  • 12 Geier A, Beery R, Haimsohn M, Karasik A. Insulin-like growth factor-1 inhibits cell death induced by anticancer drugs in the MCF-7 cells: involvement of growth factors in drug resistance.  Cancer Invest. 1995;  13 480-486
  • 13 Sell C, Baserga R, Rubin R. Insulin-like growth factor I (IGF-I) and the IGF-I receptor prevent etoposide-induced apoptosis.  Cancer Res. 1995;  55 303-306
  • 14 Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin).  J Natl Cancer Inst. 2001;  93 1852-1857
  • 15 Chakravarti A, Loeffler J S, Dyson N J. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling.  Cancer Res. 2002;  62 200-207
  • 16 McMenamin M E, Soung P, Perera S, Kaplan I, Loda M, Sellers W R. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage.  Cancer Res. 1999;  59 4291-4296
  • 17 Chang Q, Li Y, White M F, Fletcher J A, Xiao S. Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications.  Cancer Res. 2002;  62 6035-6038
  • 18 Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B, Baserga R. Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis.  Mol Cell Biol. 1999;  19 7203-7215
  • 19 Brodt P, Fallavollita L, Khatib A M, Samani A A, Zhang D. Cooperative regulation of the invasive and metastatic phenotypes by different domains of the type I insulin-like growth factor receptor beta subunit.  J Biol Chem. 2001;  276 33 608-33 615
  • 20 Leventhal P S, Feldman E L. Insulin-like growth-factors as regulators of cell motility - signaling mechanisms.  Trends Endocrinol Metab. 1997;  8 1-6
  • 21 Playford M P, Bicknell D, Bodmer W F, Macaulay V M. Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin.  Proc Natl Acad Sci USA. 2000;  97 12 103-12 108
  • 22 Xie Y, Skytting B, Nilsson G, Brodin B, Larsson O. Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype.  Cancer Res. 1999;  59 3588-3591
  • 23 Samani A A, Fallavollita L, Jaalouk D E, Galipeau J, Brodt P. Inhibition of carcinoma cell growth and metastasis by a vesicular stomatitis virus G-pseudotyped retrovector expressing type I insulin-like growth factor receptor antisense.  Hum Gene Ther. 2001;  12 1969-1977
  • 24 Zhang D, Brodt P. Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling.  Oncogene. 2003;  22 974-982
  • 25 Tang Y, Zhang D, Fallavollita L, Brodt P. Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor.  Cancer Res. 2003;  63 1166-1171
  • 26 Lopez T, Hanahan D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis.  Cancer Cell. 2002;  1 339-353
  • 27 Kaplan P J, Mohan S, Cohen P, Foster B A, Greenberg N M. The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model.  Cancer Res. 1999;  59 2203-2209
  • 28 Reiss K, Wang J Y, Romano G, Furnari F B, Cavenee W K, Morrione A, Tu X, Baserga R. IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation.  Oncogene. 2000;  19 2687-2694
  • 29 Pennisi P A, Barr V, Nunez N P, Stannard B, Le Roith D. Reduced expression of insulin-like growth factor I receptors in MCF-7 breast cancer cells leads to a more metastatic phenotype.  Cancer Res. 2002;  62 6529-6537
  • 30 Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine I D, Belfiore A, Vigneri R. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells.  Mol Cell Biol. 1999;  19 3278-3288
  • 31 Sciacca L, Mineo R, Pandini G, Murabito A, Vigneri R, Belfiore A. In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A.  Oncogene. 2002;  21 8240-8250
  • 32 Camirand A, Lu Y, Pollak M. Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells.  Med Sci Monit. 2002;  8 BR521-526
  • 33 Ullrich A, Gray A, Tam A W, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le Bon T, Kathuria S, Chen E. et al . Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity.  Embo J. 1986;  5 2503-2512
  • 34 Favelyukis S, Till J H, Hubbard S R, Miller W T. Structure and autoregulation of the insulin-like growth factor 1 receptor kinase.  Nat Struct Biol. 2001;  8 1058-1063
  • 35 De Meyts P, Whittaker J. Structural biology of insulin and IGF1 receptors: implications for drug design.  Nat Rev Drug Discov. 2002;  1 769-783
  • 36 Garcia-Echeverria C, Brueggen J, Caparo H-G, Evans D B, Ferrari S, Fabbro D, Furet P, Geiger T, Liebetanz J, Marti A, Martiny-Baron G, Mestan J, Pearson M A, Ruetz S, Stolz B, Hofmann F. Characterization of potent and selective kinase inhibitors of IGF-IR.  Proc Amer Assoc Cancer Res. 2003;  44 1008
  • 37 Elbashir S M, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.  Nature. 2001;  411 494-498
  • 38 Crooke S T. Molecular mechanisms of action of antisense drugs.  Biochim Biophys Acta. 1999;  1489 31-44
  • 39 Stein C A. The experimental use of antisense oligonucleotides: a guide for the perplexed.  J Clin Invest. 2001;  108 641-644
  • 40 Kozak M. Features in the 5' non-coding sequences of rabbit alpha and beta-globin mRNAs that affect translational efficiency.  J Mol Biol. 1994;  235 95-110
  • 41 Ambrose D, Resnicoff M, Coppola D, Sell C, Miura M, Jameson S, Baserga R, Rubin R. Growth regulation of human glioblastoma T98G cells by insulin-like growth factor-1 and its receptor.  J Cell Physiol. 1994;  159 92-100
  • 42 Resnicoff M, Coppola D, Sell C, Rubin R, Ferrone S, Baserga R. Growth inhibition of human melanoma cells in nude mice by antisense strategies to the type 1 insulin-like growth factor receptor.  Cancer Res. 1994;  54 4848-4850
  • 43 Resnicoff M, Sell C, Rubini M, Coppola D, Ambrose D, Baserga R, Rubin R. Rat glioblastoma cells expressing an antisense RNA to the insulin-like growth factor-1 (IGF-1) receptor are nontumorigenic and induce regression of wild-type tumors.  Cancer Res. 1994;  54 2218-2222
  • 44 Samani A A, Zhu L, Nalbantoglu J, Brodt P. Retroviral transduction with antisense IGF-IR RNA inhibits glioblastoma growth and induces dormancy in an orthotopic brain tumor model.  Proc Amer Assoc Cancer Res. 2003;  44 6505
  • 45 Burfeind P, Chernicky C L, Rininsland F, Ilan J. Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo.  Proc Natl Acad Sci USA. 1996;  93 7263-7168
  • 46 Lee C T, Wu S, Gabrilovich D, Chen H L, Nadafrahrov S, Ciernik I F, Carbone D P. Antitumor effects of an adenovirus expressing antisense insulin-like growth-factor-I receptor on human lung-cancer cell-lines.  Cancer Res. 1996;  56 3038-3041
  • 47 Liu X, Turbyville T, Fritz A, Whitesell L. Inhibition of insulin-like growth factor I receptor expression in neuroblastoma cells induces the regression of established tumors in mice.  Cancer Res. 1998;  58 5432-5438
  • 48 Chernicky C L, Yi L, Tan H, Gan S U, Ilan J. Treatment of human breast cancer cells with antisense RNA to the type I insulin-like growth factor receptor inhibits cell growth, suppresses tumorigenesis, alters the metastatic potential, and prolongs survival in vivo [In Process Citation].  Cancer Gene Ther. 2000;  7 384-395
  • 49 Nakamura K, Hongo A, Kodama J, Miyagi Y, Yoshinouchi M, Kudo T. Down-regulation of the insulin-like growth factor I receptor by antisense RNA can reverse the transformed phenotype of human cervical cancer cell lines.  Cancer Res. 2000;  60 760-765
  • 50 Scotlandi K, Maini C, Manara M C, Benini S, Serra M, Cerisano V, Strammiello R, Baldini N, Lollini P L, Nanni P, Nicoletti G, Picci P. Effectiveness of insulin-like growth factor I receptor antisense strategy against Ewing's sarcoma cells.  Cancer Gene Ther. 2002;  9 296-307
  • 51 Shapiro D N, Jones B G, Shapiro L H, Dias P, Houghton P J. Antisense-mediated reduction in insulin-like growth factor-I receptor expression suppresses the malignant phenotype of a human alveolar rhabdomyosarcoma.  J Clin Invest. 1994;  94 1235-1242
  • 52 Sun H Z, Wu S F, Tu Z H. Blockage of IGF-1R signaling sensitizes urinary bladder cancer cells to mitomycin-mediated cytotoxicity.  Cell Res. 2001;  11 107-115
  • 53 Hellawell G O, Ferguson D J, Brewster S F, Macaulay V M. Chemosensitization of human prostate cancer using antisense agents targeting the type 1 insulin-like growth factor receptor.  BJU Int. 2003;  91 271-277
  • 54 Turner B C, Haffty B G, Narayanan L, Yuan J, Havre P A, Gumbs A A, Kaplan L, Burgaud J L, Carter D, Baserga R, Glazer P M. Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation.  Cancer Res. 1997;  57 3079-3083
  • 55 Macaulay V M, Salisbury A J, Bohula E A, Playford M P, Smorodinsky N I, Shiloh Y. Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase.  Oncogene. 2001;  20 4029-4040
  • 56 Shiloh Y. ATM and related protein kinases: safeguarding genome integrity.  Nat Rev Cancer. 2003;  3 155-168
  • 57 Trojan J, Johnson T R, Rudin S D, Ilan J, Tykocinski M L. Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA.  Science. 1993;  259 94-97
  • 58 Trojan J, Duc H T, Upegui-Gonzalez L C, Hor F, Guo Y, Anthony D, Ilan J. Presence of MHC-I and B-7 molecules in rat and human glioma cells expressing antisense IGF-I mRNA.  Neurosci Lett. 1996;  212 9-12
  • 59 Choudhury A, Seliger B, Bock M, Charo J, Kiessling R. siRNA mediated downregulation of Her-2/neu oncogene upregulates MHC class I in Her-2/neu overexpressing tumor cells.  Proc Amer Assoc Cancer Res. 2003;  44 6503-n
  • 60 Andrews D W, Resnicoff M, Flanders A E, Kenyon L, Curtis M, Merli G, Baserga R, Iliakis G, Aiken R D. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas.  J Clin Oncol. 2001;  19 2189-2200
  • 61 Hammond S M, Caudy A A, Hannon G J. Post-transcriptional gene silencing by double-stranded RNA.  Nat Rev Genet. 2001;  2 110-119
  • 62 Gil J, Esteban M. Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action.  Apoptosis. 2000;  5 107-114
  • 63 Kumar M, Carmichael G G. Antisense RNA: function and fate of duplex RNA in cells of higher eukaryotes.  Microbiol Mol Biol Rev. 1998;  62 1415-1434
  • 64 Dudley N R, Labbe J C, Goldstein B. Using RNA interference to identify genes required for RNA interference.  Proc Natl Acad Sci USA. 2002;  99 4191-4196
  • 65 Harborth J, Elbashir S M, Bechert K, Tuschl T, Weber K. Identification of essential genes in cultured mammalian cells using small interfering RNAs.  J Cell Sci. 2001;  114 4557-4565
  • 66 Ohta T, Essner R, Ryu J H, Palazzo R E, Uetake Y, Kuriyama R. Characterization of Cep135, a novel coiled-coil centrosomal protein involved in microtubule organization in mammalian cells.  J Cell Biol. 2002;  156 87-99
  • 67 Bohula E A, Salisbury A J, Sohail M, Playford M P, Riedemann J, Southern E M, Macaulay V M. The efficacy of small interfering RNAs targeted to the type 1 IGF receptor is influenced by secondary structure in the IGF1R transcript.  J Biol Chem. 2003;  278 15991-15997
  • 68 Donis-Keller H. Site specific enzymatic cleavage of RNA.  Nucleic Acids Res. 1979;  7 179-192
  • 69 Wraight C J, White P J, McKean S C, Fogarty R D, Venables D J, Liepe I J, Edmondson S R, Werther G A. Reversal of epidermal hyperproliferation in psoriasis by insulin-like growth factor I receptor antisense oligonucleotides.  Nat Biotechnol. 2000;  18 521-526
  • 70 Lima W F, Monia B P, Ecker D J, Freier S M. Implication of RNA structure on antisense oligonucleotide hybridization kinetics.  Biochemistry. 1992;  31 12 055-12 061
  • 71 Michel F, Westhof E. Modelling of the three-dimensional architecture of group I catalytic introns based on comparative sequence analysis.  J Mol Biol. 1990;  216 585-610
  • 72 Sohail M, Akhtar S, Southern E M. The folding of large RNAs studied by hybridization to arrays of complementary oligonucleotides.  RNA. 1999;  5 646-655
  • 73 Sohail M, Southern E M. Oligonucleotide scanning arrays: application to high-throughput screening for effective antisense reagents and the study of nucleic acid interactions.  Adv Biochem Eng Biotechnol. 2002;  77 43-56
  • 74 Fire A, Xu S, Montgomery M K, Kostas S A, Driver S E, Mello C C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. .  Nature. 1998;  391 806-811
  • 75 Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T. Single-stranded antisense siRNAs guide target RNA cleavage in RNAi.  Cell. 2002;  110 563-n
  • 76 Bertrand J-R, Pottier M, Vekris A, Opolon P, Maksimenko A, Malvy C. Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo.  Biochem Biophys Res Commun. 2002;  296 1000-1004
  • 77 Lamberton J, Christian A. Varying the nucleic acid composition of siRNA molecules dramatically varies the duration and degree of gene silencing.  Mol Biotechnol. 2003;  24 111-120
  • 78 McCaffrey A P, Meuse L, Pham T T, Conklin D S, Hannon G J, Kay M A. RNA interference in adult mice.  Nature. 2002;  418 38-39
  • 79 Brummelkamp T R, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference.  Cancer Cell. 2002;  2 243-247
  • 80 Wilda M, Fuchs U, Wossmann W, Borkhardt A. Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi).  Oncogene. 2002;  21 5716-5724
  • 81 Filleur S, Courtin A, Ait-Si-Ali S, Guglielmi J, Merle C, Harel-Bellan A, Clezardin P, Cabon F. SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth.  Cancer Res. 2003;  63 3919-3922
  • 82 Yao X, Hu J F, Daniels M, Shiran H, Zhou X, Yan H, Lu H, Zeng Z, Wang Q, Li T, Hoffman A R. A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinoma.  J Clin Invest. 2003;  111 265-273
  • 83 Opalinska J B, Gewirtz A M. Nucleic-acid therapeutics: basic principles and recent applications.  Nat Rev Drug Discov. 2002;  1 503-514
  • 84 Shaw L C, Afzal A, Lewin A S, Timmers A M, Spoerri P E, Grant M B. Decreased expression of the insulin-like growth factor 1 receptor by ribozyme cleavage.  Invest Ophthalmol Vis Sci. 2003;  44 4105-4113
  • 85 Chen Z, Ge Y, Landman N, Kang J X. Decreased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells.  BMC Cancer. 2002;  2 18
  • 86 Guo N, Ye J J, Liang S J, Mineo R, Li S L, Giannini S, Plymate S R, Sikes R A, Fujita-Yamaguchi Y. The role of insulin-like growth factor-II in cancer growth and progression evidenced by the use of ribozymes and prostate cancer progression models.  Growth Horm IGF Res. 2003;  13 44-53
  • 87 Rininsland F, Johnson T R, Chernicky C L, Schulze E, Burfeind P, Ilan J. Suppression of insulin-like growth factor type I receptor by a triple-helix strategy inhibits IGF-I transcription and tumorigenic potential of rat C6 glioblastoma cells.  Proc Natl Acad Sci USA. 1997;  94 5854-5859
  • 88 Macaulay V. Oligonucleotide therapies. In: Yarnold JR, Stratton M, McMillan TJ, (eds.) Molecular Biology for Oncologists. 2nd ed. London; Chapman and Hall 1996: 275-292
  • 89 Helene C, Thuong N T, Harel-Bellan A. Control of gene expression by triple helix-forming oligonucleotides. The antigene strategy.  Ann N Y Acad Sci. 1992;  660 27-36
  • 90 Yakar S, Liu J L, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I.  Proc Natl Acad Sci USA. 1999;  96 7324-7329
  • 91 Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even P C, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice.  Nature. 2003;  421 182-187
  • 92 Feldman E L, Sullivan K A, Kim B, Russell J W. Insulin-like growth factors regulate neuronal differentiation and survival.  Neurobiol Dis. 1997;  4 201-214
  • 93 Garcia-Segura L M, Cardona-Gomez G P, Chowen J A, Azcoitia I. Insulin-like growth factor-I receptors and estrogen receptors interact in the promotion of neuronal survival and neuroprotection.  J Neurocytol. 2000;  29 425-437
  • 94 Baserga R. The insulin-like growth-factor-I receptor - a key to tumor growth?.  Cancer Res. 1995;  55 249-252
  • 95 Erickson R P. Antisense transgenics in animals.  Methods. 1999;  18 304-310
  • 96 Drevs J, Medinger M, Schmidt-Gersbach C, Weber R, Unger C. Receptor tyrosine kinases: the main targets for new anticancer therapy.  Curr Drug Targets. 2003;  4 113-121
  • 97 Eckstein F. Phosphorothioate oligodeoxynucleotides: what is their origin and what is unique about them?.  Antisense Nucleic Acid Drug Dev. 2000;  10 117-121
  • 98 Tortora G, Ciardiello F. Protein kinase A type I: a target for cancer therapy.  Clin Cancer Res. 2002;  8 303-304
  • 99 Monia B P, Holmlund J, Dorr F A. Antisense approaches for the treatment of cancer.  Cancer Invest. 2000;  18 635-650
  • 100 Jansen B, Zangemeister-Wittke U. Antisense therapy for cancer - the time of truth.  Lancet Oncol. 2002;  3 672-683
  • 101 Horton J. Trastuzumab use in breast cancer: clinical issues.  Cancer Control. 2002;  9 499-507
  • 102 Ludwig D L, Burtrum D, Lu D, Anderson D M, Prewett M, Bassi R, Koo H, Jimenez X, Pereira D S, Apblett R, Kussie P, Bohlen P, Hicklin D J, Zhu Z, Witte L. A fully human monoclonal antibody to the human IGF-1 receptor that blocks ligand-dependent signaling and inhibits the growth of multiple human tumors in nude mice.  Proc Amer Assoc Cancer Res. 2003;  44 761

Dr. V. Macaulay

Cancer Research UK Laboratories · Weatherall Institute of Molecular Medicine ·

Headley Way, Headington · Oxford OX3 9DS UK

Phone: + 44 (1865) 222433

Fax: + 44 (1865) 222431 ·

Email: macaulay@cancer.org.uk