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Supportive Oncology Utku_v1_A4_book_01_2011 14/12/2011 15:10 Page 228 Supportive Oncology The End of Cytotoxics? Nalân Utku Private Lecturer, Institute for Medical Immunology, Charité University Hospital Berlin 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: 5 May 2011 Accepted: 6 September 2011 Citation: European Oncology & Haematology, 2011;7(4):228–33 DOI: 10.17925/EOH.2011.07.04.228 Correspondence: Nalân Utku, Institut für Medizinische Immunologie, Charité Universitätsmedizin Berlin, Campus Virchow-Clinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E: [email protected] Cancer is characterised by uncontrolled and unlimited multiplication Cytotoxic drugs have been used for many years and most physicians of cells outpacing the natural rate of cell death (apoptosis).1 The are used to handling them. There is a large amount of data on their treatment of cancer involves cytotoxic or targeted therapeutics that safety and efficacy, and a wide range of combination regimens for kill the cancer cells, stop their multiplication, inhibit metastasis or many different types of cancers. These drugs also tend to be low-cost break tolerance against cancer cells by modulating T-regulatory cells because many of them are available in generic forms. or antigen-presenting/T-cell recognition via vaccination (see Figure 1). The main groups of cytotoxic drugs are: 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, • alkylating agents; predicted to rise to around 12 million in 2030.2 This increase is driven • topoisomerase inhibitors; by an ageing population, rising levels of obesity and the increasing • anthracyclines and other cytotoxic antibiotics; use of tobacco and alcohol in both the developing and the developed • antimetabolites; and world. The treatment of cancer is therefore a growing market. The • antimicrotubule or antitubulin agents. 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 This first section of the article provides a brief introduction on the action of the different types of cytotoxic agents. What are Cytotoxic Drugs? Cytotoxic drugs were the first form of cancer chemotherapy to be Alkylating Agents established. They act by destroying rapidly dividing cells. The Alkylating agents are the most widely used cytotoxic drugs and they earliest use of cytotoxics can be traced back to nitrogen mustard, target the DNA in cancer cells. They include the nitrogen mustards which was used to treat squamous cell carcinoma.1 Nitrogen and platinum-based drugs, which are used in more than 50 % of mustard was derived from mustard gas and developed (but never combination treatment regimens.7 The other key groups of alkylating used) as a poisonous gas in World War I. It is thought that it was agents are the aziridines, alkyl sulphonates and nitrosoureas.1 first used to treat cancer as early as 1942. In results published in 1946, patients with haematopoietic disorders, including Hodgkin’s Alkylating agents covalently bond with DNA strands, preventing DNA disease, lymphosarcoma and leukaemia, showed improvements replication and potentially limiting RNA replication and protein after treatment with nitrogen mustard; some were even able to go production. Bifunctional alkylating agents cross-link between DNA back to work. Nitrogen mustard was most effective in treating strands (inter-strand) or within DNA strands (intra-strand); Hodgkin’s disease, with one patient showing a good response for monofunctional alkylating agents do not form cross links. Once the DNA 33 months.4–6 is damaged, this inhibits cell-cycle progression and either the cell dies or 228 © TOUCH BRIEFINGS 2011 Utku_v1_A4_book_01_2011 14/12/2011 15:10 Page 229 The End of Cytotoxics? the DNA is repaired. Enhanced ability to repair DNA cross links in tumour Figure 1: Approaches to Treating Cancer cells may explain the development of resistance to alkylating agents.1 Cytotoxics Blockade of metastasis The most widely used alkylating agents include the nitrogen mustards cyclophosphamide and ifosfamide, which have bifunctional alkylating metabolites.8 The platinum-based agent cisplatin was first assessed Tumour as an antitumour agent in 1969. Cisplatin forms DNA adducts, leading to cell death, but its mechanism of action is still not clear.9 Aziridines, such as thiotepa and mitomycin C, are activated by enzymes and form inter-strand cross links.1 Busulphan is a widely used example of the Induction of Regulatory T cells alkyl sulphonates, and forms inter-strand cross links, as does immune response the nitrosourea carmustine.1 Table 1: Side Effects Associated with Cytotoxic Agents Topoisomerase Inhibitors Topoisomerase inhibitors wind and unwind DNA during DNA Cytotoxic Agent Side Effect replication and protein synthesis, and inhibiting these enzymes leads Alkylating agents Increased risk of acute non-lymphocytic leukaemia 12 to cell death. For example, topoisomerase II induces transient Anthracyclines, taxanes Accumulation can lead to severe side effects, thus double-strand breaks during DNA replication and transcription, and and bleomycin need for setting a ‘lifetime dose’ 8,13 then catalyses strand break repair. Inhibiting topoisomerase II Anthracyclines • Acute and chronic cardiotoxicity 12 prevents the strand break repair, leading to programmed cell death.10 • Carcinogenicity/mutagenicity For example, the topoisomerase II inhibitor etoposide acts by Vinca alkaloids Neurotoxicities such as peripheral or autonomic 12 stabilising the DNA–topoisomerase II complex.11 neuropathy Taxanes • Hypersensitivity reactions 14 • Neuropathy14 Topoisomerase I inhibitors, such as camptothecin and camptothecin Platinum-based Nephrotoxicity 7 derivatives, inhibit the relegation stage of the nicking–closing reaction compounds catalysed by topoisomerase I, leaving the enzyme covalently Antifolates Acute renal failure 8 complexed with DNA.11 Anthracyclines and Other Cytotoxic Antibiotics Antimicrotubule or Antitubulin Agents The earliest antitumour antibiotic, actinomycin A, dates back to the The taxanes and vinca alkaloids act by disrupting the assembly of 1930s. Actinomycin A was isolated from Streptomyces. Anthracycline microtubules, which are involved in cytokinesis, mitosis and antibiotics have a number of targets in the cell. They bind to DNA and vesicular transport.8 intercalate in the major groove of the double helix, which may cause the double helix to unwind by separating purine and pyrimidine bases. Paclitaxel was the first taxane on the market, and was isolated from They also bind to RNA, proteins and lipids, interfering with the the bark of the Pacific yew tree Taxus brevifolia. Taxanes interrupt cell replication of DNA, the transcription and translation of DNA, and division and cause cell cycle arrest.8 Docetaxel is a semi-synthetic inhibiting enzymes and affecting membrane function.10 analogue of paclitaxel. Anthracycline antibiotics also inhibit topoisomerase II, which induces The original vinca alkaloids, vincristine and vinblastine, were isolated transient double-strand breaks during DNA replication and transcription, from Vinca rosea L, the periwinkle plant. These vinca alkaloids and then catalyses strand break repair. Inhibiting topoisomerase II interfere with the balance between tubulin and microtubules and prevents strand break repair, leading to programmed cell death.10 prevent mitosis, which triggers apoptosis.8 Follow-up vinca alkaloids include vindesine and vinorelbine. Anthracenedione antibiotics such as mitoxantrone intercalate into the double helix and act as topoisomerase II inhibitors.10 Actinomycins, for Disadvantages of Cytotoxic Agents example actinomycin D, intercalate between base pairs in DNA and lie Cytotoxic agents are associated with toxicity because of their mode in the minor groove of DNA. Actinomycin D forms a very stable complex of action. Cytotoxics attack all rapidly dividing cells, including with single- and double-stranded DNA, inhibiting RNA and protein healthy cells and cancer cells, and so they can cause side effects synthesis.10 Mitomycin C forms DNA inter-strand cross links and inhibits by damaging normal rapidly dividing cells. This causes hair loss, DNA replication, and the bleomycins cause
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