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Plant-Derived Cytostatic Drugs

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Plant-Derived Cytostatic Drugs GinPolMedProject © 4 (50) 2018: 044-049 • REVIEW ARTICLE Plant-derived cytostatic drugs Anna Antosz-Gruszkoś Regional Specialist Hospital Megrez Sp. z o. o. – Hospital pharmacy, Tychy AUTHORS’ CONTRIBUTION: (A) Study Design · (B) Data INTRODUCTION Collection · (C) Statistical Analysis · (D) Data Interpre- tation · (E) Manuscript Preparation · (F) Literature Se- Neoplastic and cardiovascular diseases are the arch · (G) Funds Collection leading causes of mortality both in Poland and worldwide. Based on the epidemiological data Neoplastic diseases represent the leading causes of mortality in developed countries. A number of pharmacological me- of the Polish Union of Oncology and Institute thods are used to treat neoplasms, and chemotherapy is the of Oncology in Warsaw, which follow WHO most commonly applied method of systemic therapy. Plant- reports, the number of new cancer cases is pro- SUMMARY derived cytostatic drugs used to treat neoplastic diseases include: cytotoxic antibiotics, podophyllotoxin derivatives, jected to double to 20 million, cancer-related antimicrotubule agents, camptothecin derivatives and enzy- mortality will increase to 70% and complica- mes. Anthracyclines: doxorubicin or mitoxantrone, and other tions of cancer will increase from 6 to 10 antibiotics, such as bleomycin, dactinomycin and mitomycin, are of great importance among plant-derived antibiotics. The million to the year 2020. These data clearly above mentioned drugs are mainly used against hematologic illustrate the scale of the problem and empha- malignancies and solid tumors. The examples of plant-derived size how mandatory it is to create a new and compounds whose derivatives are administered to treat some of the neoplasms are podophyllotoxin derived from Podophyl- effective system of cancer treatment [1]. lum pelatum and Podophyllum emodi as well as camptothe- Neoplasm (neoplasma) is, according to cin isolated from Camptotheca acuminata. Inhibition of ma- Williams’ definition, a group of abnormal cells lignant growth by disturbing the activity of the mitotic spin- dle, or more precisely by halting an incorrect process of that grow excessively in the host organism due mitosis, applies to Vinca alkaloids, taxanes and epothilones. to uncontrolled cell divisions. This excessive Interactions with microtubules of the spindle apparatus are growth is induced by continuous and unstop- most commonly used to treat such neoplasms as ovarian cancer, breast cancer and Hodgkin lymphoma. Asparaginase pable cell proliferation, even when the trigger- is an essential and fundamental enzyme used in chemothe- ing factor has been eliminated. Cell prolifera- rapy of acute lymphoblastic leukemia and also of other tion is accompanied by cell differentiation dis- malignancies, such as non-Hodgkin lymphomas. The applica- tion of cytostatic agents is exceedingly limited because of their orders, which are harmful and pointless for the frequent toxicity for healthy cells. Nevertheless, the above organism. A neoplasm may develop from each mentioned plant-derived compounds are successfully used in tissue capable of replication. Carcinogenesis is treatment of many malignancies. Furthermore, comprehensi- ve clinical trials on cytostatic drugs contribute to the impro- a complex and multistep process that usually vement of their characteristics, antineoplastic potential and takes many years with no specific symptoms for safety of chemotherapy. a long time [2]. Three phases of carcinogenesis Key words: chemotherapy; cytostatic drugs; cancer; hospital pharmacy have been distinguished: initiation, promotion and progression. In the first phase – initiation Address for correspondence: Anna Antosz-Gruszkoś – the carcinogenic factor acts upon a healthy Regional Specialist Hospital Megrez Sp. z o.o. – Hospital cell causing a genetic mutation that is fixed in Pharmacy, Edukacji 102, 43-100 Tychy, Poland e-mail: [email protected] subsequent divisions. As a result, the expression of genes engaged in cell cycle regulation: pro- Word count: 2861 Tables: 0 Figures: 0 References: 17 to-oncogenes, suppressor genes or mutator genes, is impaired or enhanced. The promotion Received: 12.11.2018 Accepted: 18.11.2018 phase is characterized by the accumulation of Published: 19.12.2018 genetic and epigenetic changes that lead to conversion of a mutated cell into a neoplastic cell. An altered cell undergoes uncontrolled divisions and becomes resistant to signals direct- ing it towards apoptotic death. This stage may last even several years. The last phase of car- cinogenesis is progression during which a neo- plasm develops and gains the ability to infiltrate tissues and metastasize. This process may last from several months to several years. 44 A. Antosz-Gruszkoś – Plant-derived cytostatic drugs Methods of pharmacological treatment of plastic action and cardiotoxicity. Anthracycline cancer encompass chemotherapy, hormonal antibiotics, being ones of the more important therapy and immunotherapy. Chemotherapy is anti-cancer medications, are used in treatment the most widely used method and one of the of hematologic neoplasms and solid tumors. fundamental methods of systemic treatment. It Doxorubicin, also called adriamycin, is charac- is used for the treatment of disseminated can- terized by very good pharmacokinetic proper- cers, inoperable tumors and hematologic neo- ties: a rapid distribution phase and a slow elim- plasms, e.g. leukemia of various types. It is ination phase. DOX has a broad spectrum of crucial in cancer treatment and can be applied action and is used for the treatment of leuke- as postoperative therapy or treatment adjuvant mias, breast cancer, lymphomas, sarcomas and to hormonal therapy, immunotherapy or radi- often in multidrug therapies. Adverse effects of ation therapy. doxorubicin include nausea, vomiting, bone Chemotherapy consists in eradicating cancer marrow damage and alopecia, but the most cells by administering cytostatic or cytotoxic serious adverse effect is cardiotoxicity in the drugs to the patient. Cytostatics are anti-cancer form of arrhythmias, conduction disorders and medications that destroy rebel cancer cells by cardiomyopathy. The second cytostatic drug, blocking the cell cycle and activating genetical- i.e. daunorubicin, is produced from Streptomy- ly programmed cell death mechanisms (apop- ces peucetius. It rapidly permeates to tissues tosis). Plant-derived chemotherapeutic agents from blood after intravenous administration. It have contributed to cancer therapy develop- is metabolized in the liver to an active dauno- ment and its progress [3]. rubicinol compound. Due to significant car- diotoxicity, daunorubicin is currently used in CLASSIFICATION OF PLANT-DERI- the treatment of acute lymphoblastic and my- eloid leukemia. With time, other anthracycline VED CYTOSTATICS medications have appeared, namely epirubicin Cytostatic medications are a very heterogeneous and idarubicin, but neither of them has a more group of compounds in terms of both structure potent anticancer effect than doxorubicin or and mechanism of action. The best explored daunorubicin and neither meets the expecta- and the most widely used cytostatics are alky- tions regarding cardiotoxicity reduction. Pira- lating agents, antimetabolites and plant-derived rubicin, aclarubucin and zoribicin are used in medications, classified on the basis of the mech- anticancer treatment of acute myeloid, myelo- anism of action. Plant-derived cytostatic drugs blastic and lymphoblastic leukemias as well as constitute over 60% of antineoplastic medica- in organ cancers and lymphomas [4,5]. The final tions and can be divided into: cytostatic anti- synthetic compound belonging to second gen- biotics, podophyllotoxin derivatives, antimicro- eration anthracyclines in the group of cytostat- tubule agents, camptothecin derivatives and ic antibiotics is mitoxantrone (MTX), charac- enzymes. terized by anticancer, immunosuppressive and immunomodulating effects. This drug reduces Cytostatic antibiotics the activity of type II topoisomerase, damages Cytostatic antibiotics of the greatest relevance DNA as well as inhibits T cells, B cells, mac- are anthracycline compounds that can be divid- rophages and antibody production. MTX is ed into the first generation drugs (doxorubicin used in the treatment of leukemia, breast can- (DOX), daunorubicin) and second generation cer, liver cancer, ovarian carcinoma, prostate drugs (epirubicin, idarubicin, pirarubicin, acla- cancer and gastric carcinoma. It is also used in rubicin, zoribicin and mitoxantrone). Anthracy- patients with secondary progressive and relaps- clines are cell cycle phase-specific substances ing-remitting multiple sclerosis. High cardiotox- that were first isolated about 50 years ago from icity is also the factor that limits the use of Streptomyces perceturs and Streptomyces case- mitoxantrone in anticancer therapy. Cardiotox- sius. Their mechanism of action consists in icity induced by anthracyclines can be counter- binding with the double DNA helix by inhib- acted by Dexrazoxane (Cardioxane) that, by iting type II topoisomerase, RNA and DNA chelating intracellular iron, prevents the forma- polymerases, helicases and DNA-repairing en- tion of anthracycline–iron complexes, which, in zymes. These compounds cause the production consequence, inhibits the formation of oxygen of free radicals, thus inducing cell oxidative free radicals, thereby protecting the myocardi- stress, which is responsible for their anti-neo- um from damage [6,7]. 45 © GinPolMedProject
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