European Journal of Clinical Pharmacology

, Volume 67, Issue 5, pp 437–447

Drug therapy of cancer

Review Article


Cancer chemotherapy was introduced at the same time as antibacterial chemotherapy but has not been nearly such a success. However, there is a growing optimism in oncology today due to the introduction of several more or less target-specific drugs as complements to the conventional cytotoxic drugs introduced half a century ago. The success in the treatment of chronic myelogenous leukemia by imatinib, inhibiting the bcr-abl-activated tyrosine kinase and thereby interrupting the signal transduction pathways that lead to leukemic transformation with impressive survival benefit, has paved the way for this new optimism. Another success story is the introduction of trastuzumab in breast cancers overexpressing the HER-2 receptor. In contrast, there has been little progress in other malignancies such as metastatic malignant melanoma, although very recently, clinical trials with new targeted drugs have shown increased survival. All major pharmaceutical companies now have ambitious development programs in the cancer area. However, the high costs of the novel drugs cause economic distress in the health care system in many countries leading to an intense debate on the cost-effectiveness of these drugs in relation to other health care activities.


Cancer treatment Cytotoxic drugs Targeted drugs Tyrosine kinase inhibitors Monoclonal antibodies 


  1. 1.
    Ferlay J, Autier P, Boniol M et al (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592PubMedCrossRefGoogle Scholar
  2. 2.
    Berrino F, De Angelis R, Sant M et al (2007) Survival for eight major cancers and all cancers combined for European adults diagnosed in 1955-99: results of the EUROCARE-4 study. Lancet Oncol 8:773–783PubMedCrossRefGoogle Scholar
  3. 3.
    Shoemaker RH (2006) The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6:813–823PubMedCrossRefGoogle Scholar
  4. 4.
    Mellor HR, Callaghan R (2008) Resistance to chemotherapy in cancer: a complex and integrated cellular response. Pharmacology 81:275–300PubMedCrossRefGoogle Scholar
  5. 5.
    Kaye SB (2008) Reversal of drug resistance in ovarian cancer: where do we go from here? J Clin Oncol 26:2616–2618PubMedCrossRefGoogle Scholar
  6. 6.
    Rosenberg B, Van Camp L, Grimley EB et al (1967) The inhibition of growth or cell division in Escherichia coli by different ionic species of platinum(IV) complexes. J Biol Chem 242:1347–1352PubMedGoogle Scholar
  7. 7.
    Rosenberg B, VanCamp L, Trosko JE et al (1969) Platinum compounds: a new class of potent antitumour agents. Nature 222:385–386PubMedCrossRefGoogle Scholar
  8. 8.
    Minotti G, Menna P, Salvatorelli E et al (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRefGoogle Scholar
  9. 9.
    Heidelberger C, Ansfield FJ (1963) Experimental and clinical use of fluorinated pyrimidines in cancer chemotherapy. Cancer Res 23:1226–1243PubMedGoogle Scholar
  10. 10.
    Elion GB (1989) The purine path to chemotherapy. Science 244:41–47PubMedCrossRefGoogle Scholar
  11. 11.
    Plunkett W, Heinemann V, Estey E, Keating M (1990) Pharmacologically directed design of leukemia therapy. Haematol Blood Transfus 33:610–613PubMedGoogle Scholar
  12. 12.
    Carmichael J (1998) The role of gemcitabine in the treatment of other tumors. Br J Cancer 78(suppl 3):21–25PubMedCrossRefGoogle Scholar
  13. 13.
    McLeod HL, Cassidy J, Powrie RH et al (2000) Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034. Clin Cancer Res 6:2677–2684PubMedGoogle Scholar
  14. 14.
    Vogelzang NJ, Rusthoven JJ, Symanowski J et al (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644PubMedCrossRefGoogle Scholar
  15. 15.
    Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551PubMedCrossRefGoogle Scholar
  16. 16.
    Petrelli F, Borgonovo K, Barni S (2010) Targeted delivery for breast cancer therapy: the history of nanoparticle-albumin-bound paclitaxel. Expert Opin Pharmacother 11:1413–1432PubMedCrossRefGoogle Scholar
  17. 17.
    De Bono JS, Oudard S, Ozguroglu M (2010) Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). J Clin Oncol 28:15s, abstract 4508Google Scholar
  18. 18.
    Gautschi O, Heighway J, Mack PC et al (2008) Aurora kinases as anticancer drug targets. Clin Cancer Res 14:1639–1648PubMedCrossRefGoogle Scholar
  19. 19.
    Skipper H, Schabel F, Wilcox W (1964) Experimental evaluation of potential anticancer agents. Cancer Chemother Rep 35:1–111PubMedGoogle Scholar
  20. 20.
    De Vita VT, Serpick A, Carbone PP (1970) Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 73:881–895Google Scholar
  21. 21.
    Einhorn L (2002) Curing metastatic testicular cancer. Proc Nat Acad Sci USA 99:4592–4595PubMedCrossRefGoogle Scholar
  22. 22.
    Bonadonna G, Brusamolino E, Valagussa P et al (1976) Combined chemotherapy as adjuvant treatment in operable breast cancer. N Engl J Med 294:405–410PubMedCrossRefGoogle Scholar
  23. 23.
    Bonadonna G, Moliterni A, Zambetti M et al (2005) 30 Years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ 330:217PubMedCrossRefGoogle Scholar
  24. 24.
    Druker BJ, Lydon NB (2000) Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 105:3–7PubMedCrossRefGoogle Scholar
  25. 25.
    Druker B, Guilhot F, O’Brian S et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–2417PubMedCrossRefGoogle Scholar
  26. 26.
    Pollack VA, Savage DM, Baker DA et al (1999) Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358, 774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739–748PubMedGoogle Scholar
  27. 27.
    Baselga J, Averbuch SD (2000) ZD1839 ('Iressa') as an anticancer agent. Drugs 60(suppl 1):33–40PubMedCrossRefGoogle Scholar
  28. 28.
    Cappuzzo F, Ciuleanu T, Stelmakh L et al (2010) Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521–529PubMedCrossRefGoogle Scholar
  29. 29.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124PubMedCrossRefGoogle Scholar
  30. 30.
    Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134PubMedCrossRefGoogle Scholar
  31. 31.
    Demetri GD, van Oosterom AT, Garrett CR et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338PubMedCrossRefGoogle Scholar
  32. 32.
    Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–90PubMedCrossRefGoogle Scholar
  33. 33.
    Hamilton M, Wolf JL, Rusk J et al (2006) Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 12:2166–2171PubMedCrossRefGoogle Scholar
  34. 34.
    Köhler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–7PubMedCrossRefGoogle Scholar
  35. 35.
    Grillo-López AJ, White CA, Varns C et al (1999) Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 5(Suppl 14):66–73Google Scholar
  36. 36.
    Goldenberg MM (1999) Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Ther 2:309–318CrossRefGoogle Scholar
  37. 37.
    Garnock-Jones KP, Keating GM, Scott LJ (2010) Trastuzumab: a review of its use as adjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Drugs 70:215–239PubMedCrossRefGoogle Scholar
  38. 38.
    Folkman J (1972) Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175:409–416PubMedCrossRefGoogle Scholar
  39. 39.
    Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400PubMedCrossRefGoogle Scholar
  40. 40.
    Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedCrossRefGoogle Scholar
  41. 41.
    Van Cutsem E, Köhne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1742PubMedCrossRefGoogle Scholar
  42. 42.
    Soulières D, Greer W, Magliocco AM et al (2010) KRAS mutation testing in the treatment of metastatic colorectal cancer with anti-EGFR therapies. Curr Oncol 17(Suppl 1):S31–40PubMedGoogle Scholar
  43. 43.
    Rowinsky EK, Schwartz GH, Gollob JA (2004) Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 22:3003–15PubMedCrossRefGoogle Scholar
  44. 44.
    Wolchok JD, Neyns B, Linette G (2010) Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11:155–64PubMedCrossRefGoogle Scholar
  45. 45.
    O'Day FS, Hodi DF, McDermott RW et al (2010) A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma. J Clin Oncol 28:18sGoogle Scholar
  46. 46.
    Flaherty KT, Puzanov I, Kim KB et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819PubMedCrossRefGoogle Scholar
  47. 47.
    Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z et al (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977PubMedCrossRefGoogle Scholar
  48. 48.
    Sparks CA, Guertin DA (2010) Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 29:3733–3744PubMedCrossRefGoogle Scholar
  49. 49.
    Houghton PJ (2010) Everolimus. Clin Cancer Res 16:1368–1372PubMedCrossRefGoogle Scholar
  50. 50.
    Yin L, Velazquez OC, Liu ZJ (2010) Notch signaling: emerging molecular targets for cancer therapy. Biochem Pharmacol 80:690–701PubMedCrossRefGoogle Scholar
  51. 51.
    Gualberto A, Pollak M (2009) Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28:3009–21PubMedCrossRefGoogle Scholar
  52. 52.
    Murnane JP (2010) Telomere loss as a mechanism for chromosome instability in human cancer. Cancer Res 70:4255–9PubMedCrossRefGoogle Scholar
  53. 53.
    Shay JW, Keith WN (2008) Targeting telomerase for cancer therapeutics. Br J Cancer 98:677–83PubMedCrossRefGoogle Scholar
  54. 54.
    Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–66PubMedCrossRefGoogle Scholar
  55. 55.
    Nahi H, Selivanova G, Lehmann S et al (2008) Mutated and non-mutated TP53 as targets in the treatment of leukaemia. Br J Haematol 141:445–453PubMedCrossRefGoogle Scholar
  56. 56.
    Lambert JM, Gorzov P, Veprintsev DB et al (2009) PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15:376–388PubMedCrossRefGoogle Scholar
  57. 57.
    Herrstedt J (2008) Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 5:32–43PubMedCrossRefGoogle Scholar
  58. 58.
    Hesketh PJ (2001) Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting. Support Care Cancer 9:350–354PubMedCrossRefGoogle Scholar
  59. 59.
    Murgo AJ, Kummar S, Rubinstein L et al (2008) Designing phase 0 cancer clinical trials. Clin Cancer Res 14:3675–3682PubMedCrossRefGoogle Scholar
  60. 60.
    Hamburger AW, Salmon SE (1977) Primary bioassay of human tumor stem cells. Science 197:461–463PubMedCrossRefGoogle Scholar
  61. 61.
    Glas AM, Floore A, Delahaye JMJ et al (2006) Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics 7:278PubMedCrossRefGoogle Scholar
  62. 62.
    Dewit O, Starkel P, Roblin X (2010) Thiopurine metabolism monitoring: implications in inflammatory bowel diseases. Eur J Clin Invest 40:1037–1047Google Scholar
  63. 63.
    Desta Z, Ward BA, Soukhova NV, Flockahart DA (2004) Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A4 and CYP2D6. J Pharmacol Exp Ther 310:1062–1075PubMedCrossRefGoogle Scholar
  64. 64.
    Howell A, Cuzick J, Baum M et al (2005) Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60–62PubMedCrossRefGoogle Scholar
  65. 65.
    Richardson MA, Sanders T, Palmer JL et al (2000) Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol 18:2505–2514PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyUniversity HospitalLinköpingSweden
  2. 2.Department of OncologyUniversity HospitalLinköpingSweden

Personalised recommendations