The cell cycle is divided into four phases. In the S-phase DNA is copied. Then the genetic material is split into two different cells during the division in the M-phase (mitosis). The G1 and G2-phase are phases of relative rest between synthesis and mitosis.
Alkylating agents: not phase dependent
Antimetabolites: S-phase
Antimiotics: M phase
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| cell cycle and cytostatics |
Alkylating cytostatics act by alkylation with nucleophilic substituion of DNA. Thereby the interstrand cross-links are formed, which are toxic to the cell. Moreover the interstrand cross-links inhibit DNA replication. The helicases which unwind the DNA under normal conditions are not able to break the cross-links.
Non-classical alkylating agents/platinium containing cytostatic drug: cisplatin, carbiplatin, oxaliplatin
Other alkylating agents: cyclophosphamine, iphosphamide
Common side effects: vomiting, nausea, myelosuppression, cystitis and damage of mucous membranes.
Antimetabolites
Antimetabolites mimic the action of normal metabolites in the folic acid cycle and the metabolic pathway. It interferes with normal synthesis of nucleic acids by falsely substituting purines and pyrimidines in metabolic pathways.
Folic acid antagoinists, e.g. methotrexate. MTX is a competitive inhibitor of the dihydrofolate reductase enzyme.
Pyrimidine antagoinsts, 5-Fluorouracil. 5-FU binds to the thymidine synthase enzyme and thus blocks the formation of thymidine for DNA synthesis. Capecitabine is an orgal prodrug of 5-FU. Side effects of 5-FU include mucositis, myelosuppression and diarrhea.
Antimiotics
Vinca-alkaloids e.g. vincristine, vinblastine, vinorelbine. Vinca-alkaloids block cells in mitosis by disturbing microtubule synthesis via binding to tubulin and inactivating it. They prevent the assembly of microtubules and thus the formation of the spindles, resulting in a cell cycle arrest in the M phase.
Side effects: vomiting, nausea, myelosupression and neurotoxicity.
Taxanes (Paclitaxel, docetaxel) also bind to microtubules, but causing an opposite effect compared to vincalkaloids: they enhance all aspects of tubulin polymerisation irreversibly. They stabilize the microtubules by inhibiting their depolymerisation. The microtubules become rigid and non-functional.
Side effects: peripheral oedema, alopecia, bone marrow suppression, hypersensitivy reactions and cardiac disturbances,
Strand-breakage agents
Strand-breakage agents (bleomycin) also known as antitumor antibiotics binds to reduced iron and produces single and double strand DNA breaks by free radical formation. And so gaps, deletions and DNA fargments. Bleomycin is one of the few drugs that does not cause myelosuppression as an adverse effect.
Side-effect: pulmonary fibrosis, fever, dermatological problems.
Topoisomerase inhibitors
Topoisomerase inhibitors e.g. doxorubicin, epirubicine. Topoisomerase enzymes can unwind cut and ligate DNA. Topoisomerase I is able to cleave one strand and is thus required for DNA replication and RNA transcription. Topoisomerase II can break double strand DNA and helps DNA unwind when necessary. It has a crucial role in completion of mitosis, DNA replication and RNA transcription.
By binding nuclear chromatin, doxorubicin can form a complex between DNA and the topoisomerase II enzyme to produce strand cleavage. Inhibition of topoisomerase II enzyme results in decreased capacity for DNA repair. A second mechanism of DNA damaging is free radical formation, which causes many single- and double strand breaks.
Etoposide is a specific topoisomerase II inhibitor. The mechanism of action mainly involves the induction of double strand DNA breaks by interaction with DNA topoisomerase II inhibitor, by reversible stabilizing the cleavage complex and the formation of free radicals. The result is arrest of the cell cycle in late S or early G2 phase or apoptosis
Side-effects: myelosuppression, nausea, vomiting, alopecia.
Topotecan and irinotecan are specific topoisomerase I inhibitors. They stabilize the topoisomerase I-DNA complex, thereby causing DNA breaks and finally cell death.
Side effects: bone marrow suppression resulting in severe neutropenia, diarrhea, chilnergic syndrome.
Cytostatic drug-induced emesis
Many cytotoxic drugs induce severe emesis. The emesis can be triggered directly via the circularion, because the chemo trigger zine is just outside the blood brain barrier. Cytotoxic drugs can also induce emesis by stimulating the release of 5HT from enterochromaffin cells in the upper GI tract.
Two main kinds of emesis:
- Acute emesis: begins 1-2 hours after onset of chemo and last 8-24 hours
- Delayed emesis: beings usually 24-72h after chemo.
Low risk of emesis: no prophylatic therapy recommended, single doses of metoclopramide or dexamethasone as needed,
Moderate risk of emesis: prophylaxis with a single day of therapy with 5HT3 receptor antagonist and dexamethasone. Refractory emesis? additional D2 antagonst, metoclopramine.
High risk of emesis: prophylaxis of dexamethasone, 5TH3 antagonist followed by daily oral dexamethasone and 3-4 times daily metoclopramide.
Cisplatin induced high risk emesis: dexamthasone + aprepitant
TUMORS AND HORMONES
Steroid hormones serve essential functions in the human body. When cells that have steroid receptors become cancerous, exposure to steroids increases the cancer's growth.
Antihormones
Antihormones block the binding site of hormone receptors in hormone-sensitive tumors, thereby inhibiting binding of the endogenous hormone and thus the growth of the tumor cell.
Tamoxifen blocks the estrogen receptors on the surface of cancer cells.
Side effects: menupausal symtoms ( hotflashes, irregular mestrual periods, vaginal discharge). Long-term use of tamoxifen increases the number of blood clots (cataracts) and the risk of developing uterine cancer.
Fulvestrant is an estrogen receptor antagonist. It binds and degrades estrogen receptors.
Side effects: hot flushes, GI complains.
Cyproterone acetate blocks the testosterone receptor competitively.
Side effects: inhibition of spermatogenesis, hepatotoxicity
Bicalutamine blocks the testosterone receptor.
Side effects: hot flushes, gynaecomastia
Aromastase inhibitors
Aromastase inhibitors (anastrozole, letrozole) act by blocking the conversion of steroid precursors to their active form by inhibiting the aromatase enzyme. Aromastase inhibitors are now used as a first-line treatment for metastatic disease in postmenopausal women.
Side effects: hot flushes, increased perspiration, osteoporosis, arthralgia.
It can be wise to add biphosphonates to aromastase inhibitors in order to decrease the risk of osteoporosis
Progestagens
Progestagens (megestrol acetate, medroxyprogesterone acetate)are applied as antitumor therapy for breast and endometrial cancer in case other hormonal therapies failed. Progestagens can have a direct antitumor effect mediated via the progesterone receptor. Indirectly progestagens can inhibit the production of androgens in the adrenal gland.
LHRH-analogues
Luteinising hormone (LH) from the pituitary gland stimulates the testes to produce testosterone. LH in tunr is released upon stimulation by LHRH by the hypothalamus. An LHRH-analogue (Goserelin, Buserelin), evokes a brief increase in testosterone levels in the first few days of starting the treatment because of the increased LH release. However the pituitary will become short of LH and the LH levels will drop soon and so the levels of testosterone fall.
Side effects: hot flushes, decreased libido, gynaecomastia, weight gain, nausea.
ANTIBODY TREATMENT
Monoclonal antibodies can mark tumor cells on the outside by binding to specific proteins (receptors) The antibody makes the tumor cell recognizable for the immune attack. By another approach certain antibodies target and destroy proteins in the circulation that make the cancer grow.
Trastuzumab
Trastuzumab (Herceptin) is a monoclinal antibody directed against the human epidermal growth factor receptor-2 (HER-2). This receptor is is transcribed from a proto-oncogene and expressed on the surface of 25-35% of primary mamma carcinomas. By binding the HER-2 receptor, trastuzumab inhibits both the proliferation of the tumor cell and it mediates antibody dependent cellular cytotoxicity by natural killer cells and macrophages at the tumor cell. Trastuzumab is not very toxic for humans: it can cause cardiomyopathy in 2-3% of the patients.
Cetuximab
About one-third of all epithelial cancer express high levels of epidermal growth factor rceeptor (EGF-R). Expression of EGF-R in a tumor is an indicator of poor prognosis, decreased survival and increased metastasis. Cetuximab is a monoclonal antibody directed against this EGF-R. By binding to this receptor, cetuximab blocks phophorylation and activation of kinases in signal transduction.
Bevacizumab
Tumor growth is dependent on angiogenesis. This process is driven by the release of pro-angiogenic signals, such as vascular endothelial growth factor (VEGF) and facilitates tumor growth and increases metastatic potential.
Bevacizumab is an antiangiogenesis drug, this antibody binds directly to VEGF and prevents the interaction of VEGF with its receptors VEGFR-1 and CEGFR-2. Bevacizumab also causes existing vessels to regress, leaving the vasculature unable to support tumor growth.
Side effects: hypertension, proteinuria and bleeding.
Anti-HER2 Mechanisms of Approved HER2 Inhibitors door mednotez
PROTEIN KINASE INHIBITORS
Imatinib
Imatinib is an inhibitor of the protein tyrosine kinase, This enzyme plays a major role in the signal transduction. By blocking the signal transduction, imatinib inhibits proliferation and even induces apoptosis
Side effects: headache, nausea, vomiting, diarrhea and dyspepsia
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