Approaches to New Drug Discovery

  • Lawrence M. Kauvar


For this survey, current approaches to the discovery of new anticancer drugs are discussed in three categories: tumor-directed delivery vehicles, screens for specific protein modulators, and mechanism-blind assays. These approaches are intertwined in several respects (Fig. 12–1). New methods for identifying tumor markers provide novel delivery “addresses” as well as novel targets for drug inhibition or activation. Conversely, proteins identified by genetic epidemiology or cell biology studies as potential intervention points may also provide new addresses. In addition, random screening of novel compounds in cell-based assays, especially natural products, continues to uncover new drug targets. Moreover, cell-based cytotoxicity screening has reached a level of sophistication that allows compounds to be evaluated for novelty in their spectrum of activity before committing to the full expense of clinical development. Closing the loop, gene-transfer technology has provided cell-based screening with new power as a target validation tool, conveniently extendable to animal models via tumor-directed delivery approaches. An important conclusion from this survey is that the logic of current research is increasing the desirability of tailoring treatment protocols to patients stratified by multiple criteria.


Drug Discovery Phage Display Technology Arginine Side Chain Tumor Physiology Transfected Chinese Hamster Ovary Cell 
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  1. 1.
    Chang AE, Shu S: Current status of adoptive immunotherapy of cancer. Crit Rev Oncol Hematol 1996, 22: 213–228.PubMedCrossRefGoogle Scholar
  2. Rosok MJ, Yelton DE, Harris LJ, et al.: A combinatorial library strategy for the rapid humanization of anticarcinoma BR96 Fab. J Biol Chem 1996, 271:22611–22618.PubMedCrossRefGoogle Scholar
  3. 3.
    Jakobovits A: Production of fully human antibodies by transgenic mice. Curr Opin Biotechnol 1995, 6: 561–566.PubMedCrossRefGoogle Scholar
  4. 4.
    Marks C, Marks JD: Phage libraries: a new route to clinically useful antibodies. N Engl J Med 1996, 335: 730–733.PubMedCrossRefGoogle Scholar
  5. Maloney DG, Liles TM, Czerwinski DK, et al.: Phase I trial using escalating single dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994, 84:2457–2466.PubMedGoogle Scholar
  6. 6.
    Peterson JA, Couto JR, Taylor MR, Ceriani RL: Selection of tumor-specific epitopes on target antigens for radioimmunotherapy of breast cancer. Cancer Res 1995, 55: 5847s - 5851s.PubMedGoogle Scholar
  7. Sharkey RM, Juweid M, Shevitz J, et al.: Evaluation of a complementarity-determining region grafted (humanized) anti-carcinoembryonic antigen monoclonal antibody in preclinical and clinical studies. Cancer Res 1995, 55:5935s-5945s.PubMedGoogle Scholar
  8. Hu P, Hornick JL, Glasky MS, et al.: A chimeric Lym1/interleukin 2 fusion protein for increasing tumor vascular permeability and enhancing antibody uptake. Cancer Res 1996, 56:4998–5004.PubMedGoogle Scholar
  9. 9.
    Chen FM, Epstein AL, Li Z, Taylor CR: A comparative autoradiographic study demonstrating differential intratumor localization of monoclonal antibodies to cell surface (Lym-1) and intracellular (TNT-1) antigens. J Nucl Med 1990, 31: 1059–1066.PubMedGoogle Scholar
  10. 10.
    Yokota T, Milenic DE, Whitlow M, Schlom J: Rapid tumor penetration of a single chain Fv and comparison with other immunoglobulin forms. Cancer Res 1992, 52: 3402–3408.PubMedGoogle Scholar
  11. 11.
    Larson SM, Divgi CR, Scott AM: Overview of clinical radioimmunodetection of human tumors. Cancer 1994, 73 (3 suppl): 832–835.PubMedCrossRefGoogle Scholar
  12. Trail PA, Willner D, Knipe J, et al.: Effect of linker variation on the stability, potency, and efficacy of carcinoma-reactive BR64-doxorubicin immunoconjugates. Cancer Res 1997,57:100–105.PubMedGoogle Scholar
  13. 13.
    Melton RG, Sherwood RF: Antibody-enzyme conjugates for cancer therapy. J Natl Cancer Inst 1996, 88: 153–165.PubMedCrossRefGoogle Scholar
  14. Schuitmaker JJ, Baas P, van Leengoed HL, et al.: Photodynamic therapy: a promising new modality for the treatment of cancer. J Photochem Photobiol B 1996, 34:3–12.PubMedCrossRefGoogle Scholar
  15. Satyam A, Hocker MD, Kane-Maguire KA, et al.: Design, synthesis, and evaluation of latent alkylating agents activated by glutathione S-transferase. J Med Chem 1996, 39:1736–1747.PubMedCrossRefGoogle Scholar
  16. Nishimura T, Newkirk K, Sessions RB, et al.: Immunohistochemical staining for glutathione S-transferase predicts response to platinum-based chemotherapy in head and neck cancer. Clin Cancer Res 1996,2:1859–1865.PubMedGoogle Scholar
  17. 17.
    Sung C, van Osdol WW: Pharmacokinetic comparison of direct antibody targeting with pretargeting protocols based on streptavidin-biotin binding. J Nucl Med 1995, 36: 867–876.PubMedGoogle Scholar
  18. 18.
    Sachs L: The control of growth and differentiation in normal and leukemic blood cells. Cancer 1991, 65: 2196–2206.CrossRefGoogle Scholar
  19. Baldwin RL, Kobrin MS, Tran T, et al.: Cytotoxic effects of TGF-α-Pseudomonas exotoxin A fusion protein in human pancreatic carcinoma cells. Pancreas 1996, 13:16–21.PubMedCrossRefGoogle Scholar
  20. Huang X, Molema G, King S, et al.: Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 1997, 275:547–550.Google Scholar
  21. 21.
    Lee JH, Naito M, Tsuruo T: Non-enzymatic reductive activation of a mitomycin analog by thiols. Cancer Res 1994, 54: 2398–2403.PubMedGoogle Scholar
  22. Bischoff JB, Kirn DH, Williams A, et al.: An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996, 274:373–376.PubMedCrossRefGoogle Scholar
  23. Dean N, McKay R, Miraglia L, et al.: Inhibition of human tumor cell lines in nude mice by an antisense oligonucleotide inhibitor of protein kinase C-a expression. Cancer Res 1996, 56:3499–3507.PubMedGoogle Scholar
  24. Ning S, Macleod K, Abra RM, et al.: Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy. Int J Radiat Oncol Biol Phys 1994, 29:827–834.PubMedCrossRefGoogle Scholar
  25. 25.
    Vyas SP, Singh R, Asati RK: Liposomally encapsulated diclofenac for sonophoresis induced systemic delivery. J Microencapsul 1995, 12: 149–154.PubMedCrossRefGoogle Scholar
  26. 26.
    Ho RJY, Rouse BT, Huang L: Target sensitive immunoliposomes. Biochemistry 1986, 25: 5500–5506.PubMedCrossRefGoogle Scholar
  27. 27.
    Mitelman F, Mertens F, Johansson B: A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet 1997, 15: 417–474.PubMedCrossRefGoogle Scholar
  28. 28.
    Broach JR, Thorner J: High-throughput screening for drug discovery. Nature 1996, 7 (suppl): 14–16.Google Scholar
  29. 29.
    Mitchison TJ: Towards a pharmacological genetics. Chem Biol 1994, 1: 3–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Lyttle MH: Combinatorial chemistry: a conservative perspective. Drug Dey Res 1995, 35: 230–236.CrossRefGoogle Scholar
  31. Raymond E, Djelloul S, Buquet-Fagot C, et al.: Synergy between the non-classical thymidylate synthase inhibitor AG337 (Thymitaq) and cisplatin in human colon and ovarian cancer cells. Anticancer Drugs 1996, 7:752–757.PubMedCrossRefGoogle Scholar
  32. Zhao B, Helms LR, des Jarlais RL, et al.: A paradigm for drug discovery using a conformation from the crystal structure of a presentation scaffold. Nature Struct Biol 1995, 12:1131–1137.CrossRefGoogle Scholar
  33. Kauvar LM, Higgins DL, Villar HO, et al.: Predicting ligand binding to proteins by affinity fingerprinting. Chem Biol 1995, 2:107–118.PubMedCrossRefGoogle Scholar
  34. Wrighton NC, Farrell FX, Chang R, et al.: Small peptides as potent mimetics of the protein hormone erythropoietin. Science 1996, 273:458–463.PubMedCrossRefGoogle Scholar
  35. 35.
    Farrar MA, Alberola-Ila J, Perlmutter RM: Activation of the Raf-1 kinase cascade by coumermycin induced dimerization. Nature 1996, 383: 178–181.PubMedCrossRefGoogle Scholar
  36. 36.
    Arnold A: Moving promising research findings to the clinic: methodological issues in the design and conduct of clinical trials of retinoids. Int J Cancer 1997, 70: 467–469.PubMedCrossRefGoogle Scholar
  37. Walker S, Landovitz R, Ding WD, et al.: Cleavage behavior of calicheamicin -yI and calicheamicin T. Proc Natl Acad Sci U S A 1992, 89:4608–4612.PubMedCrossRefGoogle Scholar
  38. 38.
    Strahl C, Blackburn EH: Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines. Mol Cell Biol 1996, 16: 53–65.PubMedGoogle Scholar
  39. 39.
    Von Hoff DD: He’s not going to talk about in vitro predictive assays again, is he? J Natl Cancer Inst 1990, 82: 96–101.CrossRefGoogle Scholar
  40. 40.
    Fruehauf JP, Bosanquet AG: In vitro determination of drug response: a discussion of clinical applications. In Cancer, Principles and Practice of Oncology, 4th ed. Edited by DeVita VT Jr, Hellman S, Rosenberg SA. Philadelphia: JB Lippincott; 1993: 1–16.Google Scholar
  41. 41.
    Jakoby WB, Ziegler DM: The enzymes of detoxication. J Biol Chem 1990, 265: 20715–20718.PubMedGoogle Scholar
  42. 42.
    Montali JA, Wheatley JB, Schmidt DE Jr: Comparison of GST levels in predicting the efficacy of a novel alkylating agent. Cell Pharmacol 1996, 2: 241–247.Google Scholar
  43. 43.
    Mounts WM, Liebman MN: Qualitative modeling of normal blood coagulation and its pathological states using stochastic activity networks. Int J Biol Macromol 1997, 20: 265–281.PubMedCrossRefGoogle Scholar
  44. 44.
    Sager R: Expression genetics in cancer. Proc Natl Acad Sci U S A 1997, 94: 952–955.PubMedCrossRefGoogle Scholar
  45. Roninson IB, Gudkov AV, Holzmayer TA, et al.: Genetic suppressor elements: new tools for molecular oncology. Cancer Res 1995, 55:4023–4028.Google Scholar
  46. 46.
    Meinwald J, Eisner T: The chemistry of phyletic dominance. Proc Natl Acad Sci U S A 1995, 92: 14–18.PubMedCrossRefGoogle Scholar
  47. 47.
    Taunton J, Hassig CA, Schreiber SL: A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 1996, 272: 408–411.PubMedCrossRefGoogle Scholar
  48. 48.
    Weinstein JN, Myers TG, O’Connor PM, et al.: An information intensive approach to the molecular pharmacology of cancer. Science 1997, 275:343–349.Google Scholar
  49. 49.
    Tew KD: Genetic polymorphisms of detoxification enzymes. Cell Pharmacol 1996, 3: 143–152.Google Scholar
  50. 45.
    Ratain MJ, Mick R, Janisch L, et al.: Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender. Pharmacogenetics 1996, 6:93–101.PubMedCrossRefGoogle Scholar
  51. 51.
    Lockhart DJ, Dong H, Byrne MC, et al.: Expression monitoring by hybridization to high-density oligonucleotide arrays. Nature Biotech 1996, 14:1675–1680.CrossRefGoogle Scholar
  52. 52.
    Liao SK, Meranda C, Avner BP, et al.: Immunohistochemical phenotyping of human solid tumors with monoclonal antibodies in devising biotherapeutic strategies. Cancer Immunol Immunother 1989, 28:77–86.PubMedCrossRefGoogle Scholar

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© Current Medicine, Inc. 2000

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  • Lawrence M. Kauvar

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