The End of Cytotoxics?

European Oncology & Haematology, 2011;7(4):228-233

Abstract:

Cytotoxic drugs were the first form of cancer chemotherapy to be established, but they can have quite severe side effects. Cytotoxics attack all rapidly dividing cells, including healthy cells and cancer cells. They can therefore cause side effects such as loss of hair, damage to the skin and mucosa, and damage to bone marrow, affecting the immune system. For this reason, the focus of some cancer research has moved from cytotoxics to targeted therapeutics, including monoclonal antibodies. Monoclonal antibodies can be very effective in patients who express the appropriate target; however, not all patients do, and some develop resistance. Monoclonal antibodies, like other biologicals, are also very costly. All is not lost for cytotoxics. Because they have been around for so long, there is an abundance of data on their modes of action. Based on these data, researchers have developed newer cytotoxics that are more effective and have fewer side effects, and approaches that deliver cytotoxics more safely or target them to tumours.
Keywords: Antigens, cancer, cytotoxics, drug delivery, monoclonal antibodies, targeting
Disclosure: Nalân Utku is Managing Director of CellAct Pharma GmbH, a biotech company focused on the development of innovative therapeutics.
Received: May 05, 2011 Accepted September 06, 2011 Citation European Oncology & Haematology, 2011;7(4):228-233
Correspondence: Nalân Utku, Institut für Medizinische Immunologie, Charité Universitätsmedizin Berlin, Campus Virchow-Clinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E: nalan.utku@charite.de

Cancer is characterised by uncontrolled and unlimited multiplication of cells outpacing the natural rate of cell death (apoptosis).1 The treatment of cancer involves cytotoxic or targeted therapeutics that kill the cancer cells, stop their multiplication, inhibit metastasis or break tolerance against cancer cells by modulating T-regulatory cells or antigen-presenting/T-cell recognition via vaccination (see Figure 1).
According to the WHO, cancer is one of the leading causes of death worldwide. There were around 7.4 million deaths from cancer in 2004, predicted to rise to around 12 million in 2030.2 This increase is driven by an ageing population, rising levels of obesity and the increasing use of tobacco and alcohol in both the developing and the developed world. The treatment of cancer is therefore a growing market. The market value was around US$50 billion in 2009, an increase of about 8 % on 2008, and about 40 % of this represented US sales.3
What are Cytotoxic Drugs?
Cytotoxic drugs were the first form of cancer chemotherapy to be established. They act by destroying rapidly dividing cells. The earliest use of cytotoxics can be traced back to nitrogen mustard, which was used to treat squamous cell carcinoma.1 Nitrogen mustard was derived from mustard gas and developed (but never used) as a poisonous gas in World War I. It is thought that it was first used to treat cancer as early as 1942. In results published in 1946, patients with haematopoietic disorders, including Hodgkin’s disease, lymphosarcoma and leukaemia, showed improvements after treatment with nitrogen mustard; some were even able to go back to work. Nitrogen mustard was most effective in treating Hodgkin’s disease, with one patient showing a good response for 33 months.4–6 Cytotoxic drugs have been used for many years and most physicians are used to handling them. There is a large amount of data on their safety and efficacy, and a wide range of combination regimens for many different types of cancers. These drugs also tend to be low-cost because many of them are available in generic forms.
The main groups of cytotoxic drugs are:
  • alkylating agents;
  • topoisomerase inhibitors;
  • anthracyclines and other cytotoxic antibiotics;
  • antimetabolites; and
  • antimicrotubule or antitubulin agents.

This first section of the article provides a brief introduction on the action of the different types of cytotoxic agents.
References:
  1. Siddik ZH, Mechanisms of action of cancer chemotherapeutic agents: DNA-interactive alkylating agents and antitumour platinum-based drugs. In: Alison MR (ed), The Cancer Handbook, New York: John Wiley & Sons, 2002;1.
  2. WHO, Cancer Fact Sheet No. 297. Geneva: World Health Organization, 2009.
  3. Business Insights, The Cancer Market Outlook to 2015: Competitive Landscape, Market Size, Pipeline Analysis, and Growth Opportunities, Business Insights, 2010.
  4. Goodman LS, Wintrobe MM, Dameshek W, et al., Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders, JAMA, 1946;132:126–32.
  5. Jacobson LO, Spurr CL, et al., Nitrogen mustard therapy; studies on the effect of methyl-bis (beta-chloroethyl) amine hydrochloride on neoplastic diseases and allied disorders of the hemopoietic system, JAMA, 1946;132:263–71.
  6. Medicine: mustard against cancer, Time Magazine, Monday 21 October, 1946.
  7. Gasser G, Ott I, Metzler-Nolte N, Organometallic anticancer compounds, J Med Chem, 2011;54:3–25.
  8. Barrett SV, Cassidy J, Conventional chemotherapeutics. In: Alison MR (ed), The Cancer Handbook, New York: John Wiley & Sons, 2002;1–4:6.
  9. Kelland L, The resurgence of platinum-based cancer chemotherapy, Nat Rev Cancer, 2007;7(8):573–84.
  10. Sparreboom A, Nooter K, Verweij J, Mechanisms of action of cancer chemotherapeutic agents: antitumour antibiotics. In: Alison MR (ed), The Cancer Handbook, New York: John Wiley & Sons, 2002;2:7–8.
  11. Koh Y, Nishio K, Saijo N, Mechanisms of action of cancer chemotherapeutic agents: topoisomerase inhibitors. In: Alison MR (ed), The Cancer Handbook, New York: John Wiley & Sons, 2002;3.
  12. BNF, Cytotoxic drugs. In: British National Formulary 61, 2011. Available at: http://bnf.org/bnf/bnf/current/4676.htm (accessed 1 December 2011).
  13. Kalyn R, Ferrier L, McKay M, Pharmacy Guide to Chemotherapy: Clinical Assessment and Review 3rd edn, British Columbia Cancer Agency, 2011. Available at: www.bccancer.bc.ca/HPI/CE/ pharmacists/guidetoprotocols.htm (accessed 5 October 2010).
  14. Vishnu P, Roy V, Safety and efficacy of nab-paclitaxel in the treatment of patients with breast cancer, Breast Cancer (Auckl), 2011;5:53–65.
  15. Brennan R, Federico S, Dyer MA, The war on cancer: have we won the battle but lost the war? Oncotarget, 2010;1(2):77–83.
  16. Broxterman HJ, Georgopapadakou NH, New cancer therapeutics: target-specific in, cytotoxics out? Drug Resist Updat, 2004;7(2):79–87.
  17. Kay P, Targeted therapies: a nursing perspective, Semin Oncol Nurs, 2006;22(1 Suppl. 1):1–4.
  18. Nelson AL, Dhimolea E, Reichert JM, Development trends for human monoclonal antibody therapeutics, Nat Rev Drug Discov, 2010;9(10):767–74.
  19. Nagavarapu U, Biological Therapies for Cancer: Technologies and Global Markets, BBC Research, April 2010. Available at: www.bccresearch.com/report/biological-therapies-cancerbio048b. html (accessed 5 October 2010).
  20. MD Becker Partners, Cancer Vaccine Therapies: Failures and Future Opportunities, 7 April 2010. Available at: http://lifesciencedigest.com/2010/04/07/cancer-vaccinetherapies-failures-and-future-opportunities/ (accessed 5 October 2010).
  21. Davis ID, Update on monoclonal antibodies for the treatment of cancer, Asia Pac J Clin Oncol, 2011;7(Suppl. 1):20–5.
  22. Wilkins DK, Begent RHJ, Antibody therapy for cancer. In: Alison MR (ed), The Cancer Handbook, New York: John Wiley & Sons, 2002;6.
  23. Kang SP and Saif MW, Infusion-related and hypersensitivity reactions of monoclonal antibodies used to treat colorectal cancer – identification, prevention, and management, J Support Oncol, 2007;5(9):451–7.
  24. Abbott Laboratories, Package Insert HUMIRA (adalimumab), 2003.
  25. Reang P, Gupta M, Kohli K, Biological Response Modifiers in Cancer, MedGenMed, 2006;8(4):33.
  26. Kute T, Lack, CM, Willingham M, et al., Development of Herceptin resistance in breast cancer cells, Cytometry A, 2004;57(2):86–93.
  27. Morris PG, Fornier MN, Novel anti-tubulin cytotoxic agents for breast cancer, Expert Rev Anticancer Ther, 2009;9(2):175–85.
  28. Berrie C, No Increased Survival With Larotaxel Versus 5-FU in Patients With Advanced Pancreatic Cancer, 2010. Available at: www.DocGuide.com (accessed 19 September 2011).
  29. Carroll J, Sanofi-Aventis Chops into R&D Budget, Drops Cancer Drug, Fierce Biotech, 10 February 2010.
  30. Kruczynski A, Hill BT, Vinflunine, the latest Vinca alkaloid in clinical development. A review of its preclinical anticancer properties, Crit Rev Oncol Hematol, 2001;40(2):159–73.
  31. Frampton JE, Moen MD, Vinflunine, Drugs, 2010;70(10):1283–93.
  32. UK Medicines Information, New drugs online report for vinflunine, April 2011. Available at: www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4092 (accessed 05/10/2011).
  33. Olver IN, Trastuzumab as the lead monoclonal antibody in advanced breast cancer: choosing which patient and when, Future Oncol, 2008;4:125–31.
  34. Vose JM, Link BK, Grossbard ML, et al., Long-term update of a phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin’s lymphoma, Leuk Lymphoma, 2005;46(11):1569–73.
  35. Wu HC, Chang DK, Peptide-mediated liposomal drug delivery system targeting tumor blood vessels in anticancer therapy, J Oncol, 2010;2010:723–798.
  36. Celgene, Pipeline, 2011. Available at: www.celgene.com/research/drug-reseasrch-anddevelopment-home.aspx (accessed 1 December 2011).
  37. Kolishetti N, Dhar S, Valencia PM, et al., Engineering of selfassembled nanoparticle platform for precisely controlled combination drug therapy, Proc Natl Acad Sci USA, 2010;107(42):17939–44.
  38. Matsumura Y, Maeda H, A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs, Cancer Res, 1986;46(12 Pt 1):6387–92.
  39. Forster RE, Small SA, Tang Y, et al., Comparison of DC Beadirinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer, J Mater Sci Mater Med, 2010;21(9):2683–90.
  40. Wang J, Chen B, Chen J, et al., Synthesis and antitumor efficacy of daunorubicin-loaded magnetic nanoparticles, Int J Nanomedicine, 2011;6:203–11.
  41. Cinti C, Taranta M, Naldi I, Grimaldi S, Newly engineered magnetic erythrocytes for sustained and targeted delivery of anti-cancer therapeutic compounds, PLoS One, 2011;6(2): e17132.
  42. Moribe K, Limwikrant W, Higashi K, Yamamoto K, Drug nanoparticle formulation using ascorbic Acid derivatives, J Drug Deliv, 2011;2011:138929.
  43. Reichert JM, Antibody-based therapeutics to watch in 2011, MAbs, 2011;3(1):76–99.
  44. News Medical, FDA denies accelerated approval of Genentech’s trastuzumab-DM1 (T-DM1) BLA for metastatic breast cancer, 27 August 2010.
  45. Elvidge S, CellAct Pharma GmbH – Targeting unmet needs in cancer and inflammation, Start-Up, November 2009.
Keywords: Antigens, cancer, cytotoxics, drug delivery, monoclonal antibodies, targeting