Prospects for the Development of Antineoplastic Therapy Based on Molecular Pathology

  • I. T. Magrath
Part of the UICC International Union Against Cancer book series (UICCI)


It is only in recent years that it has become apparent that neoplasia is frequently, and perhaps invariably, a consequence of somatic genetic aberrations [1–3]. The earliest evidence for this was provided by the demonstration of chromosomal abnormalities in hemopoietic neoplasms, which are more readily subjected to karyotypic analysis than other neoplasms [4]. With improvements in the methodology of cytogenetics, neoplasms of all kinds have been shown to be associated with non-random chromosomal abnormalities. Cytogenetic analysis can detect, however, only gross structual changes in chromosomes, and the presence of multiple karyotypic abnormalities can sometimes obscure the primary genetic abnormality. In such circumstances, if the molecular consequences of the karyotypic abnormalities have been identified (e.g., in 14;18 translocations [5]), molecular analysis may increase the likelihood of detecting genetic changes. Knowledge of the molecular changes associated with specific cytogenetic abnormalities is, of course, essential to the elucidation of the functional results of the genetic rearrangements. Moreover, many relevant genetic changes may be sufficiently subtle not to be detectable by cytogenetic analysis (e.g., mutation in a gene such as may occur in Wilms’ tumor or retinoblastoma). This new discipline, molecular pathology, is likely to become of increasing value in establishing a diagnosis. In fact, it seems entirely appropriate that definitions of individual tumors should ultimately be based upon structural genetic changes or their functional consequences. This is fast becoming a reality for chronic myeloid leukemia and Burkitt’s lymphoma, both of which are associated with chromosomal translocations which have been analyzed in detail, and which can be further subdivided according to the position of the chromosomal breakpoints, ascertained by molecular biological techniques [6, 7].


Human Epidermal Growth Factor Receptor Chronic Myeloid Leukemia Long Terminal Repeat Tyrosine Kinase Activity Oncogene Product 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mitelman F (1984) Restricted number of chromosomal regions implicated in aetiology of human cancer and leukaemia. Nature 310: 325–327PubMedCrossRefGoogle Scholar
  2. 2.
    Yunis J (1983) The chromosomal basis of human neoplasia. Science 221: 227–236PubMedCrossRefGoogle Scholar
  3. 3.
    Yunis JJ (1981) Specific fine chromosomal defects in cancer: an overview. Hum Pathol 12: 503–515PubMedCrossRefGoogle Scholar
  4. 4.
    Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson BA, Gajl-Peczalska KJ (1983) Non-random chromosome abnormalities in cancer. Cancer Res 43: 2975–2984PubMedGoogle Scholar
  5. 5.
    Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, Korsmeyer SJ (1985) Cloning the chromosomal breakpoint of t(18;14) bearing human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41: 899–906PubMedCrossRefGoogle Scholar
  6. 6.
    Shtivelman E, Lifshitz B, Gale RP, Canaani E (1985) Fused transcript of abland bcrgenes in chronic myelogluous leukemia. Nature 315: 550PubMedCrossRefGoogle Scholar
  7. 7.
    Pellici P.G., Knowles D, Magrath I et al. (1986) Chromosomal breakpoints and structural alterations of the c-myc locus differ in endemic and sporadic forms of Burkitt lymphoma. Proc Natl Acad Sci USA 83: 2984CrossRefGoogle Scholar
  8. 8.
    Magrath IT (1987) Infectious mononucleosis and malignant neoplasia. In: Schlossman D (ed) Infectious mononucleosis. Praeger, New York, pp 225–227Google Scholar
  9. 9.
    Hanto DW, Frizzera G, Gail-Peczalskakj et al. (1982) Epstein—Barr virus induced B-cell lymphoma after renal transplantation, acyclovir therapy and transition from polyclonal to monoclonal B-cell proliferation. N Engl J Med 306: 913–918PubMedCrossRefGoogle Scholar
  10. 10.
    Magrath IT (1982) Malignant lymphomas. In: Levine As (ed) Cancer in the young. Masson, New York, pp 473–574Google Scholar
  11. 11.
    Magrath IT (1986) Burkitt’s lymphoma as a human tumor model: New concepts in etiology and pathogenesis. In: Pochedly C (ed) Pediatric hematology oncology reviews. Praeger, New York, pGoogle Scholar
  12. 12.
    El-Bolkainy MN (1983) The pathology of cancer of the bilharzial bladder. Bladder Cancer 1: 83–120Google Scholar
  13. 13.
    Correa P (1982) Precursors of gestric and esophageal Cancer. Cancer 50 [Suppl 111: 2554–2565Google Scholar
  14. 14.
    Sanford KK, Parshad R, Potter M et al. (1986) Chromosomal radiosensitivity during G2 phase and susceptibility to plasmacytoma induction in mice. Curr Top Microbiol Immunol 132: 202–208PubMedCrossRefGoogle Scholar
  15. 15.
    Yunis JJ, Soreng AL (1984) Constitutive fragile sites and cancer. Science 226: 1199–1203PubMedCrossRefGoogle Scholar
  16. 16.
    Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce C (1984) Cloning the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226: 1097–1099PubMedCrossRefGoogle Scholar
  17. 17.
    Erikson J, Williams DL, Finan J, Nowell PC, Croce C (1985) Locus of the alpha-chain of the T-cell receptor is split by a translocation in T-cell leukemias. Science 229: 784–786PubMedCrossRefGoogle Scholar
  18. 18.
    Croce CM, Isobe M, Palumbo A, Puck J, Ming J, Tweardy D, Erikson J (1985) Gene for alpha-chain of human T-cell receptor involved in T-cell neoplasms. Science 227: 1044–1047PubMedCrossRefGoogle Scholar
  19. 19.
    McKeithan TW, Shima EA, Le Beau MM et al. (1986) Molecular cloning of the breakpoint junction of a human chromosomal 8:14 translocation involving the T cell receptor alpha-chain gene and sequences on the 3’ side of MYC. Proc Natl Acad Sci USA 83: 6636–6640PubMedCrossRefGoogle Scholar
  20. 20.
    Finger LR, Harvey RC, Moore RCA, et al. (1986) A common mechanism of chromosomal translocation in T and B cell neoplasia. Science 234: 982–985PubMedCrossRefGoogle Scholar
  21. 21.
    Weinberg RA (1985) The action of oncogenes in the cytoplasm and nucleus. Science 230: 770–776PubMedCrossRefGoogle Scholar
  22. 22.
    Bishop JM (1987) The molecular genetics of cancer. Science 235: 305–311PubMedCrossRefGoogle Scholar
  23. 23.
    Bartram CR et al. (1983) Translocation of c-abloncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukemia. Nature 306: 277–280PubMedCrossRefGoogle Scholar
  24. 24.
    Ben Neriah Y, Daley GQ, Mes-Masson AM et al. (1986) The chronic myelogenous leukemia-specific p210 protein is the product of the bcr/ablhybrid gene. Science 233: 212–214CrossRefGoogle Scholar
  25. 25.
    Murphree AL, Benedict WF (1984) Retinoblastoma: clues to human oncogenesis. Science 223: 1028–1033PubMedCrossRefGoogle Scholar
  26. 26.
    Fearon ER, Vogelstein B, Feinberg AP (1984) Somatic deletion and duplication of genes on chromosome 11 in Wilms’ tumors. Nature 309: 176–178PubMedCrossRefGoogle Scholar
  27. 27.
    Koufos A, Hansen MF, Copeland NG, et al. (1985) Loss of heterozygosity in three embryonal tumors suggests a common pathogenetic mechanism. Nature 316: 330–334PubMedCrossRefGoogle Scholar
  28. 28.
    Draper GJ, Sanders BM, Kingston JE (1986) Second primary malignant neoplasms in patients with retinoblastoma. Br J Cancer: 53: 661–171PubMedCrossRefGoogle Scholar
  29. 29.
    Drebin JA, Link VC, Stern DF et al. (1985) Down-modulation of an oncogene protein product and transformed phenotype by monoclonal antibodies. Cell 41: 695–706CrossRefGoogle Scholar
  30. 30.
    Feramisco JR, Clark R, Wong G et al. (1985) Transient reversion of rasoncogene-induced antibodies specific for amino-acid 12 of rasprotein. Nature 314: 639–642PubMedCrossRefGoogle Scholar
  31. 31.
    Stewart TA, Mintz B (1981) Successive generations of mice produced from an established culture line of euploid teratocarcinoma cells. Proc Natl Acad Sci USA 78: 6314–6318PubMedCrossRefGoogle Scholar
  32. 32.
    Bodner AJ, Ting RC, Gallo RC (1981) Induction of differentiation of human promyelocytic leukemia cells (HL60) by nucleosides and methotrexate. JNCI 67: 1025–1030PubMedGoogle Scholar
  33. 33.
    Griffin J, Munroe D, Major P, Kufe D (1982) Induction of differentiation of human myeloid leukemia cells by inhibitors of DNA synthesis. Exp Hematol 10: 774–781PubMedGoogle Scholar
  34. 34.
    Sartorelli AC (1985) Malignant cell differentiation as a potential therapeutic approach. Br J Cancer 52: 293–302 (The Walter Hubert Lecture)Google Scholar
  35. 35.
    Schlick E, Ruffman R, Hartung K, Chirigos MA (1985) Modulation of myelopoiesis by CSF or CSF-inducing biological response modifiers. J Immunopharmacol 7: 141–166PubMedGoogle Scholar
  36. 36.
    Matsui T, Takahashi R, Mihara K et al. (1985) Cooperative regulation of c-myc expression in differentiation of human promyelocytic leukemia induced by recombinant gamma-interferon and 1,25-dihydroxy vitamin D3. Cancer Res 4545: 4366–4371Google Scholar
  37. 37.
    Prochownik EV, Kukowska J (1986) Deregulated expression of c-myc by murine erythroleukemia cells prevents differentiation. Nature 322: 848–850PubMedCrossRefGoogle Scholar
  38. 38.
    Farid NR, Briones-Urbina R, Islam MN: Anti-idiotypic antibodies as probes for hormone-receptor interaction.Google Scholar
  39. 39.
    Kennedy RC, Melnick JL, Dreesman GR (1984) Antibody to hepatitis B virus induced by injecting antibodies to the idiotype. Science 223: 930–931PubMedCrossRefGoogle Scholar
  40. 40.
    Nishizuka Y (1984) The role of protein kinase C in cell surface signal transduction and tumor promotion. Nature 308: 693–698PubMedCrossRefGoogle Scholar
  41. 41.
    Ullrich A, Coussens L, Hayflickjs et al. (1984) Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309: 418–425PubMedCrossRefGoogle Scholar
  42. 42.
    Baccarani M, Zaccaria A, Bandini G, Cavazzini G, Fanin R, Tura S (1983) Low dose arabinosyl cytosine for treatment of pre-leukemia and acute myeloid leukemia. Leuk Res 7: 539–545PubMedCrossRefGoogle Scholar
  43. 43.
    Castaigne S, Daniel MT, Tilly H et al. (1983) Does treatment with Ara-C in low dosage cause differentiation in leukemic cells? Blood 62: 85–86PubMedGoogle Scholar
  44. 44.
    Lesley JF, Schulte RJ (1985) Inhibition of cell growth by monoclonal anti-transferrin receptor antibodies. Mol Cell Biol 5: 1814–1821PubMedGoogle Scholar
  45. 45.
    Carney DN, Cuttitta F (1986) Interruption of small cell lung cancer (SCLC) growth by a monoclonal antibody to bombesin (Abstr). 5th NCI-EORTC Symposium on New Drugs in Cancer Therapy, October 22–24, 1986, AmsterdamGoogle Scholar
  46. 46.
    Duesberg PH (1985) Activated proto-oncogenes: sufficient or necessary for cancer? Science 228: 669–676PubMedCrossRefGoogle Scholar
  47. 47.
    Nau MM, Carney DN, Battey J et al. (1984) Amplification, expression and rearrangement of c-mycand N-myc oncogenes in human lung cancer. Curr Top Microbiol Immunol 113: 172–177PubMedCrossRefGoogle Scholar
  48. 48.
    Libermann TA, Nusbaum HR, Razon N et al. (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumors of glial origin. Nature 313: 144–147PubMedCrossRefGoogle Scholar
  49. 49.
    Seeger RC, Brodeur GM, Sather H et al. (1985) Association of multiple copies of the N-myconcogene with rapid progression of neuroblastomas. N Engl J Med 313: 1111–1116PubMedCrossRefGoogle Scholar
  50. 50.
    Stark GR, Wahl GM (1984) Gene amplification. Annu Rev Biochem 53: 447PubMedCrossRefGoogle Scholar
  51. 51.
    Efstratiadis A, Posakony JW, Maniatis T et al. (1980) Structure and evolution of the human beta-globin gene family. Cell 21: 653–668PubMedCrossRefGoogle Scholar
  52. 52.
    Nakauchi H, Nolan C, Hsu H et al. (1985) Molecular cloning of Lyt-2, a membrane glycoprotein present on mouse T lymphocytes: molecular homology to its human counterpart, Leu-2/T8, and to immunoglobulin variable regions. Proc Natl Acad Sci USA 82: 5126–5130PubMedCrossRefGoogle Scholar
  53. 53.
    Williams A (1984) The immunoglobulin superfamily takes shape. Nature 308: 12–13PubMedCrossRefGoogle Scholar
  54. 54.
    Maddon PJ, Littman DR, Godfrey M et al. (1985) The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family. Cell 42: 93–104PubMedCrossRefGoogle Scholar
  55. 55.
    Shimpke RT, Brown PC, Johnston RN et al. (1983) Gene amplification and methotrexate resistance in cultured animal cells. In: Murphy SB, Gilbert JR (eds) Leukemia research: advances in cell biology and treatment. Elsevier, New York, pp 121–134Google Scholar
  56. 56.
    Brodeur GM, Hayer FA, Green AA et al. (1987) Consistent n-myccopy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients. Cancer Res 47: 4248–4253PubMedGoogle Scholar
  57. 57.
    Sager R, Gader IK, Stephens L, Grabowy CT (1985) Gene amplification: an example of accelerated evolution in tumorigenic cells. Proc Natl Acad Sci USA 82: 7015–7019PubMedCrossRefGoogle Scholar
  58. 58.
    Thiele CJ, Reynolds CP, Israel M (1985) Decreased expression of N-mycprecedes retinoic acid-induced morphological differentiation of human neuroblastoma cells. Nature 313: 404–406PubMedCrossRefGoogle Scholar
  59. 59.
    Matsui T, Takahashi R, Mihara K, et al. (1985) Cooperative regulation of c-myc expression in differentiation of human myelocytic leukemia induced by recombinant gamma-interferon and 1,25 dihydroxyvitamin D3, Cancer Res 45: 4366–4371PubMedGoogle Scholar
  60. 60.
    Knight E Jr, Anton ED, Fahey D et al. (1985) Interferon regulates c-myc gene expression in Daudi cells at the post transcriptional level. Proc Natl Acad Sci USA 82: 1151–1154PubMedCrossRefGoogle Scholar
  61. 61.
    Croce C, Erikson J, Bar-Rushdi A et al. (1984) Translocated c-myc oncogene of Burkitt lymphoma is transcribed in plasma cells and repressed in lymphoblastoid cells. Proc Natl Acad Sci USA 81: 3170–3174PubMedCrossRefGoogle Scholar
  62. 62.
    Green P, Pines O, Masayori I (1986) The role of antisense RNA in gene regulation. Annu Rev Biochem 55: 569–597PubMedCrossRefGoogle Scholar
  63. 63.
    Izant JG, Weintraub H (1984) Inhibition of thymidine kinase gene expression by anti-sense: a molecular approach to genetic analysis. Cell 36: 1007–1009PubMedCrossRefGoogle Scholar
  64. 64.
    Heikkila R, Schwag G, Wickstrom F et al. (1987) A c-mycantisense oligodeoxynucleotide inhibits entry into S phase but not progress from Go to G1. Nature 328: 445–449PubMedCrossRefGoogle Scholar
  65. 65.
    Reddy EP, Reynolds RK, Santos E, Barbacid M (1982) A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300: 149–152PubMedCrossRefGoogle Scholar
  66. 66.
    Tabin CJ, Bradley SM, Barsmann CI et al. (1982) Mechanism of activation of a human oncogene. Nature 300: 143–149PubMedCrossRefGoogle Scholar
  67. 67.
    McGrath JP, Capon DJ, Goeddel DV, Levinson A (1984) Comparative biochemical properties of normal and activated human rasprotein. Nature 310: 644–649PubMedCrossRefGoogle Scholar
  68. 68.
    Papageorge A, Lowy D, Scolnick EJ (1982) Comparative biochemical properties of p21 rasmolecules coded for by viral and cellular rasgenes. J Virol 44: 509–519PubMedGoogle Scholar
  69. 69.
    Broek D, Samiy N, Fasano O et al. (1985) Differential activation of yeast adenylate cyclase by wild-type and mutant ras proteins. Cell 41: 763–769PubMedCrossRefGoogle Scholar
  70. 70.
    Breckner SK, Hattori S, Shih TY (1985) The rasoncogene product p21 is not a regulatory component of adenylate cyclase. Nature 317: 71–72CrossRefGoogle Scholar
  71. 71.
    Spiegel AM, Gierschik P, Levine MA, Downs RW Jr (1985) Clinical implications of guanine nucleotide-binding proteins as receptor effector couplers. N Engl J Med 312: 26–33PubMedCrossRefGoogle Scholar
  72. 72.
    White MF, Maron R, Kahn CR (1985) Insulin rapidly stimulates tyrosine kinase phosphorylation of a Mr-185,000 protein in intact cells. Nature 314: 183–186CrossRefGoogle Scholar
  73. 73.
    Kamata T, Feramisco JR (1984) Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of rasoncogene proteins. Nature 310: 147–150PubMedCrossRefGoogle Scholar
  74. 74.
    Hunter T, Alexander CB, Cooper JA (1985) Protein phosphorylation and growth control. Ciba Found Symp 116: 188–204PubMedGoogle Scholar
  75. 75.
    Lax I, Bar-Elim, Yarden Y et al. (1984) Antobodies to two defined regions of the transforming protein pp 60 srcinteract specifically with the epidermal growth factor receptor kinase system. Proc Natl Acad Sci USA 81: 5911–5915PubMedCrossRefGoogle Scholar
  76. 76.
    Casnellie JE, Krebs EG (1984) The use of synthetic peptides for defining the specificity of tyrosine protein kinases. Adv Enzyme Regul 22: 501–515PubMedCrossRefGoogle Scholar
  77. 77.
    Ebina Y, Edery M, Leland E et al. (1985) Expression of a functional human insulin receptor from a cloned cDNA in chinese hamster ovary cells. Proc Natl Acad Sci USA 82: 8014–8018PubMedCrossRefGoogle Scholar
  78. 78.
    Noda M, Ko M, Ogura O et al. (1985) Sarcoma viruses carrying rasoncogenes induce differentiation associated properties in a neuronal cell line. Nature 318: 73–75PubMedCrossRefGoogle Scholar
  79. 79.
    Alema S, Casalbore P, Agostini E, Tato F (1985) Differrentiation of PC 12 phaeochromocytoma cells induced by v-srconcogene. Nature 316: 557–559PubMedCrossRefGoogle Scholar
  80. 80.
    Muller R, Wagner EF (1984) Differentiation of F9 teratocarcinoma stem cells after transfer of c-fosproto-oncogenes. Nature 311: 438–442PubMedCrossRefGoogle Scholar
  81. 81.
    Borelli E, Hen R, Chambon P (1984) Adenovirus-2 El A products repress enhancer-induced stimulation of transcription. Nature 312: 608-612CrossRefGoogle Scholar
  82. 82.
    Desplan C, Theis J, O’Farrell PH (1985) The drosophila developmental gene, engrailed, encodes a sequence-specific DNA binding activity. Nature 318: 630-635PubMedCrossRefGoogle Scholar
  83. 83.
    Chen ISA, Cann AJ, Shah NP, Gaynor RB (1985) Functional relation between HTLV-III and EI A proteins in transcriptional activation. Science 230: 570-573PubMedCrossRefGoogle Scholar
  84. 84.
    Cross SL, Feinberg MB, Wolf JB (1987) Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a non-functional promoter by the transactivating gene of HTLV-I. Cell 49: 47-56PubMedCrossRefGoogle Scholar
  85. 85.
    Friend SH, Bernards R, Rogelj S et al. (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323: 643-646PubMedCrossRefGoogle Scholar
  86. 86.
    Melton DA, Krieg PA, Rebagliati MR et al. (1984) Efficient in vitro synthesis of biologically active RNA and RNA hybridisation probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res 12: 7035-7056PubMedCrossRefGoogle Scholar
  87. 87.
    Lin FL, Sperle K, Sternberg N (1985) Recombination in mouse L cells between DNA introduced into cells and homologous chromosomal sequences. Proc Natl Acad Sci USA 82: 1391-1395PubMedCrossRefGoogle Scholar
  88. 88.
    Woychik RP, Stewart TA, Davis LG et al. (1985) An inherited limb deformity created by inser-tional mutagenesis in a transgenic mouse. Nature 318: 36-40PubMedCrossRefGoogle Scholar
  89. 89.
    Stuhlmann H, Cone R, Mulligan RC, Jaenisch R (1984) Introduction of a selectable gene into different animal tissue by a retrovirus recombinant vector. Proc Natl Acad Sci USA 81: 7151-7155PubMedCrossRefGoogle Scholar
  90. 90.
    Reddy VB, Beck AK, Garramone AJ et al. (1985) Expression of human choriogonadotropin in monkey cells using a single simian virus 40 vector. Proc Natl Acad Sci USA 82: 3644-3648PubMedCrossRefGoogle Scholar
  91. 91.
    Jahner D, Haase K, Mulligan R, Jaenisch R (1985) Insertion of the bacterial gptgene into the germ line of mice by retroviral infection. Cell Biol 82: 6927-6931Google Scholar
  92. 92.
    Adams JM, Harris AW, Pinkert CA et al. (1985) The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318: 533-538PubMedCrossRefGoogle Scholar
  93. 93.
    Landolfi NF, Capra JD, Tucker PW (1986) Interaction of cell-type-specific nuclear proteins with immunoglobulin VH promoter region sequences. Nature 323: 548-551PubMedCrossRefGoogle Scholar
  94. 94.
    Walters L (1986) The ethics of human gene therapy. Nature 320: 225-227PubMedCrossRefGoogle Scholar
  95. 95.
    Sheau-Fung Y, Von Ruden T, Kantoff PW et al. (1986) Self-inactivating retroviral vectors designed for transfer of whole genes into mammalian cells. Proc Natl Acad Sci 83: 3194-3198CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • I. T. Magrath

There are no affiliations available

Personalised recommendations