Cytostatic
Cytostatics (or cytostatics , singular cytostatics , from ancient Greek κύτος kýtos "vessel" / cell and στάσις stásis "condition") are natural or synthetic substances that inhibit cell growth or cell division . Since they work all the more the faster the cell growth takes place and thus in particular damage rapidly growing and multiplying tumor cells, they are mainly used for the treatment of cancer ( chemotherapy ) due to their antitumor effects , but sometimes also for the treatment ofAutoimmune diseases .
In addition to the classic cytostatics, other substances such as hormones , therapeutic monoclonal antibodies , cytokines and so-called “small molecules” such as signal transduction inhibitors , protease inhibitors , etc. are used today in the treatment of tumor diseases . These substances are usually not referred to as cytostatic agents because they do not directly inhibit cell division or cell growth. Monoclonal antibodies and cytokines are, for example, cancer immunotherapeutic agents .
The efficacy of cytostatics ( chemosensitivity ) can be assessed by ex vivo chemosensitivity tests before starting chemotherapy.
history
During the First World War , doctors discovered that the warfare agent sulfur mustard (mustard gas) had an antiproliferative (growth-inhibiting) effect. After the war, the less toxic nitrogen mustard (= mechlorethamine ) was developed and used as the first cytostatic drug in medicine around 1942. To date, nitrogen mustard is legal in the United States , and its derivatives are included in numerous modern treatment regimens.
The designation of the substances used for cancer therapy (especially alkylating substances, antimetabolites and certain hormones) as "cytostatics" was made according to Ludwig Heilmeyer in 1947 in analogy to the " bacterostatica " which inhibits the growth of bacteria .
The cytostatic effect of the platinum complexes was discovered by chance in 1965 during an experiment with cell cultures and a platinum electrode.
Other substances such as mitotane and the vinca alkaloids were developed in completely different areas in the pharmaceutical industry, but were noticeable in animal experiments due to their growth-inhibiting potential.
Mechanism of action
Cytostatic drugs disrupt the metabolic processes associated with cell growth or cell division. Therefore, they mainly damage rapidly growing cells such as epithelial cells (including hair root cells , mucous membrane epithelium of the mouth and gastrointestinal tract ). Since tumor cells have an increased rate of cell division and a limited repair capacity, they are somewhat more sensitive to cytostatics than healthy cells. It is this difference that enables therapy with these often highly toxic substances.
Side effects
Since the toxic effect also affects healthy cells, there are many negative side effects. In particular, the mucous membrane of the gastrointestinal tract and the blood-forming bone marrow are sensitive. Almost all cytotoxic drugs cause temporary hair loss, nausea and vomiting, and a decrease in the number of white and / or red blood cells in the blood ( myelosuppression ) to varying degrees . In addition, the individual groups of active ingredients have other, different side effects, such. B. on the central nervous system or on the sense of taste . Some cytostatic agents are themselves carcinogenic (carcinogenic) and mutagenic ( germline damaging ).
Although nowadays complex accompanying treatments are used to cytostatics, some of the therapies still have to be reduced in dose, interrupted or even canceled.
The WHO classification of side effects in terms of severity is based on the measures taken in each individual case:
- Grade 0: no side effects
- Grade 1: minor side effects
- Grade 2: general condition worsened, chemotherapeutic agents have to be reduced
- Grade 3: interruption of chemotherapy necessary
- Grade 4: inpatient hospital treatment required
- Grade 5: death from chemotherapy
The symptom complex often occurring as a side effect of the subjective fatigue of some patients treated with cytostatics, triggered by the above-mentioned changes in the blood count , is called fatigue .
Environmental relevance of cytostatics
The consumption of cytostatics is increasing and improved and individually adapted therapies with optimized accompanying medication and fewer side effects improve tolerability and enable longer therapy periods. People are getting older, making them more likely to get cancer and cancer treatments. This increases the environmental relevance through undegraded cytostatically active ingredients as well as metabolic and metabolic products. Methotrexate was first detected in the wastewater of an oncological clinic as early as the 1980s . Laboratory experiments showed that different cytostatics are not biodegradable. Cyclophosphamide , ifosfamide , cisplatin and mitomycin were found to be resistant.
In research projects and study programs of the federal states , scientists found more than 150 different drug residues in environmental samples. About the aerobic and anaerobic degradability of cytostatics in sewage treatment plants and the effect on aquatic organisms - u. a. In terms of metabolic processes, genetic damage and reproductive risk - too little is known overall.
Special cytostatic groups
Alkylating agents
Alkylating agents (alkylating agents) are the oldest cytostatics. They can transfer alkyl groups to DNA . Since the alkylating agents are provided with two or more functional groups , they can cross-link two DNA strands and thus prevent them from being correctly duplicated during cell division. The effect is based on an inhibition of DNA replication. Alkylating agents are mutagenic and carcinogenic . Its main side effects are nausea, anemia, and immunodeficiency. They are still often used for lymphoma, leukemia, breast and lung cancer and sarcoma. They are of particular importance against malignant brain tumors.
- Nitrogen mustard derivatives
- Alkyl sulfonates
- Nitrosoureas
Platinum analogs
The complex cis- [Pt (NH 3 ) 2 Cl 2 ] = cisplatin and its relatives are among the most effective chemotherapeutic agents. They also cause cross-linking of the DNA by covalently binding the platinum atom to two nucleobases. Circuit boards cause nausea, anemia, hearing, nerve and kidney damage. Their main areas of application are testicular, uterine and ovarian cancer as well as tumors of the neck region. A newer platinum analog, oxaliplatin , is currently used in colorectal cancer .
Intercalants
Intercalants bind non-covalently to the DNA and prevent the binding of the polymerases, which are used for replication and transcription of the genetic material. This means that cell division and cell function are disrupted. Because of the low rate of resistant tumors, the substances are used very often and in almost all solid tumors; they are also suitable as monotherapy for patients who cannot tolerate highly effective combinations. Nausea and anemia as well as various organ damage are its most common side effects.
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Anthracyclines
- Doxorubicin (adriamycin)
- Daunorubicin
- Epirubicin
- Idarubicin
Antibiotics
The representatives of this group of substances with antibacterial and simultaneously cytostatic effects were isolated from fungi. The mechanisms of action are different, mostly DNA crosslinking through intercalation or alkylation. They are mainly peptides , so allergic reactions can occur when using them. Other side effects are lung or liver damage. Antibiotics are often found in protocols against testicular cancer, bladder cancer, and malignant lymphoma.
- Bleomycin
- Actinomycin D (Dactinomycin)
- Mitomycin C
Mitosis inhibitors
These substances bind to tubulin , a protein macromolecule that is necessary for cell division (see mitosis ). It is used for lymphomas and leukemias, less often for solid tumors. Its most unpleasant side effect is damage to the nervous system.
- Alkaloids of the pink catharanthe ( Catharanthus roseus , former name Vinca rosea ):
- Vinorelbine
- Vincristine (Oncovin)
- Vinblastine
- Vindesine
Taxanes
A relatively new group of substances, although it was discovered in the 1960s at the National Cancer Institute in the USA through a systematic screening of 35,000 plant genera in the Pacific yew ( Taxus brevifolia ). It was only since they could be produced synthetically (1994) that taxanes became increasingly widespread in breast, prostate and lung cancer and in skin cancer, often as monotherapy. The effect is based on the formation of abnormal molecules in the cell skeleton, which prevents the normal cell division.
Topoisomerase inhibitors
The topoisomerases I and II are enzymes that selective, reversible interruptions DNA strand produced in the. The inhibition causes irregular, irreversible DNA breaks and spontaneous crosslinks. This new class of substances shows promise in solid tumors, lymphomas, brain tumors and tumors in children. However, their tendency to bone marrow depression (anemia) is feared.
- Topoisomerase I Inhibitors
- Topoisomerase II inhibitors (epipodophyllotoxins)
- Etoposide = VP16
- Teniposide = VM26
Antimetabolites
Antimetabolites are built into DNA or RNA as incorrect building blocks or prevent the correct building blocks from being built in, and thus disrupt cell division and metabolism . Its side effects are nausea and anemia, as well as kidney damage.
Colon and breast cancer and many other solid tumors as well as leukemia are the areas of application for antimetabolites. It is believed that the cells' sensitivity to radiation is increased. For this reason, 5-fluorouracil is the most important substance in radiochemotherapy .
- Folic acid antagonists
- Pyrimidine analogs
- Purine analogs
Other cytotoxic drugs
- L - asparaginase , an enzyme discovered in the serum of guinea pigs that breaks down the amino acid L-asparagine. Some leukemia cells cannot make this amino acid. The toxicity to normal cells is very low.
- Tyrosine kinase inhibitors such as imatinib , dasatinib , nilotinib . These inhibit the activity of a protein that occurs in many patients with leukemia , in particular the majority of patients with chronic myeloid leukemia , and is responsible for the abnormal rate of division of these cells. Tyrosine kinase inhibitors also work very specifically against malignant cells.
- Hydroxycarbamide (hydroxyurea) inhibits the enzyme ribonucleotide reductase and thereby the DNA synthesis. Typical areas of application are in particular myeloid leukemias (especially when there are signs of leukostasis ) and other myeloproliferative diseases such as essential thrombocythemia and polycythemia vera (rubra). The main side effect is bone marrow depression.
- Mitotane , a relative of the insecticide DDT with specific effectiveness against the metabolism of cells - including tumor cells - in the adrenal gland
- Amatoxins inhibit transcription by blocking RNA polymerase . This means that no more genetic information can get from the cell nucleus into the cytoplasm , and protein synthesis is blocked. Many parts of the organism are affected by the diverse functions of proteins .
- Altretamine inhibits DNA and RNA synthesis in the cell nucleus.
- Aromatase inhibitors such as anastrozole, exemestane or letrozole inhibit the formation of estrogen and are therefore therapeutic options for tumors such as breast cancer .
Individual evidence
- ↑ κύτος and στάσις in Wilhelm Gemoll: Greek-German school and manual dictionary . 10th, completely revised edition. Oldenbourg, Munich, Düsseldorf, Stuttgart 2006, ISBN 978-3-637-00234-0 .
- ↑ Paul Obrecht: Clinical Cancerologie. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition, ibid. 1961, pp. 352-375, here: p. 371.
- ↑ Noll-Hussong M .: How cytostatics damage the brain . InfoOncology. 2009; 12 (3): 55-7.
- ^ Waste manager medicine : Environmental relevance of CMR drugs - cytostatics in wastewater , April 28, 2017.
literature
General literature
- Klaus Aktories, Ulrich Förstermann, Franz Hofmann, Klaus Starke: General and special pharmacology and toxicology , 10th edition, Elsevier, Urban & Fischer, Munich; Jena 2009, ISBN 978-3-437-42522-6 .
- WJ Zeller, H. zur Hausen (Ed.): Onkologie . Ecomed, Landsberg 1995, loose-leaf edition
Alkylating agents
- Ulrich Meyer: The history of alkylating agents . Pharmazie in our time 35 (2), pp. 104-109 (2006), ISSN 0048-3664
Metal complexes
- Wieland Voigt, Andrea Dietrich, Hans-Joachim Schmoll: Cisplatin and its analogues . Pharmazie in our time 35 (2), pp. 134-143 (2006), ISSN 0048-3664
- Markus Galanski, Bernhard K. Keppler: Tumor-inhibiting metal compounds . Pharmazie in our time 35 (2), pp. 118-122 (2006), ISSN 0048-3664
Taxanes
- Eckhard Leistner: The biology of the taxanes . Pharmazie in our time 34 (2), pp. 98-103 (2005), ISSN 0048-3664
- Volker Bartsch: Mechanism of action of taxanes . Pharmazie in our time 34 (2), pp. 104-108 (2005), ISSN 0048-3664
ethics
- Marlies Frast: To dust or ashes. (PDF) Is a legal obligation to cremate the deceased after previous cytostatic therapy justifiable from an ethical point of view? University of Zurich, 2005, archived from the original on February 1, 2014 ; accessed on July 27, 2014 .
