Impact of DNA damage induced by anticancer drugs on both S phase and mitosis phase of the cell cycle - Essay Example

?INTRODUCTION Impact of DNA damage induced by anticancer drugs on both S phase and mitosis phase of the cell cycle. Cancer in a living tissue is a condition where cell division occurs rapidly and continuously without entering the resting stage. Such cells divide and grow in an uncontrollable and a malignant growth pattern, thus making a tumour. Many genetic changes happen when a normal cell is converted to a cancer cell (Hartwell & Kastan 1994). In a carcinoma cell the normal order and the functions of a cell are impaired and the usual limits of cell division are ignored. This condition may arise as a result of a mutation / change of the genetic sequence or due to DNA damage and it is important to note that the ‘growth fraction’ (ratio of proliferating cells to cells in resting stage) is remarkably high in carcinoma cells than in normal cells (Eidukevicius et al. 2005). Cells in any living organism grow, divide, perform their functions and gradually enter apoptosis (programmed cell death) at the end of their life cycle. This process is progressed through a ‘cell cycle’ which mainly consist of four stages as G1 (gap 1), S (synthesis), G2 (gap 2) and M (mitosis). Cell cycle regulation and cancer are intersected fields and hence treating cancer is more or less done in targeting the cell cycle (Collins et al. 1997). During G1, the cells grow in size and prepare for chromosome replication by synthesizing enzymes for the next stage. In S phase, the genomic DNA chromosomes are duplicated to produce two identical chromosomes (replication) and the G2 phase prepares the cells for cell division and synthesis cellular components required for mitosis in the proceeding stage. In the M phase, the replicated chromosomes are divided through a series of processes as Prophase, Prometaphase, Metaphase, Anaphase and Telophase. Subsequently the cell splits into two identical daughter cells with cytokinensis (Lewin 1990). These cells then enter G0 (resting) stage where they carry on their respective functions or in actively dividing tissues, they once again enter G1 stage to be further divided. Each cell cycle has check points as G1/S and G2/M that is involved in correction mechanisms to prevent any error in this system. Transition through check points are signaled by cyclones and cycline-dependent kinases (CDKs). ATM (Ataxia Telangiectasia Mutated) and ATR (Ataxia Telangiectasia and Rad-3-related) protein kinases are the leading controllers in DNA damage checkpoint signaling (Nishida et el. 2009). This mechanism ensures any error during DNA synthesis mechanism does not pass through the cell cycle. Cells with any mistake are either repaired before progressing or enter into apoptosis (programmed cell death) if the errors cannot be rectified. The G1/S check point ensures the cells have grown into the appropriate size and the DNA is not damaged while in the G2/M check point it is confirmed that the DNA is properly replicated during the S phase. Another check point in the M stage (metaphase check point), see that the chromosomes are properly aligned on the spindle at metaphase. Any mistake detected in any of these check points force the cells to repair or enter apoptosis. Chemotherapy is an efficient and a widely used method of treating cancer. Here the cancerous cells are treated with anticancer/antineoplastic drugs and apoptosis is induced (Muller et al. 1999). Usually a combination of two or more drugs is administered to the patient to increase efficiency. Chemotherapeutic treatments are targeted to destroy actively proliferating cells since cancerous cells are highly proliferating. This has the disadvantage of attacking rapidly dividing normal cells such as in the bone marrow, intestine and hair follicles and cause chemotherapy side effects as hair loss (alopecia) and inflammation in the digestive tract (mucositis) since the anticancer drugs fails to identify cancerous and normal cells but simply destroys the fast proliferating cells. Chemotherapeutic agents or anticancer drugs are mainly aimed toward cell cycle at inhibiting mitosis (impair reproduction of cells) and inducing apoptosis. They induce DNA damage and activate DNA damaging signaling cascades which result in cell cycle arrests at G1/S and G2/M check points (Nishida et al. 2009). They are grouped according to the manner in which they influence cell chemistry and according to the stage of the cell cycle it affect. Within this context, the anticancer drugs are basically grouped as ‘cell cycle specific drugs’ and ‘cell cycle non specific drugs’. Drugs grouped under ‘alkylating agents’ and ‘anthrocyclins’ belong to the cell cycle non-specific drugs. They destroy cancer cells in any phase of the cell cycle. ‘Antimetabolites’ and ‘plant alkaloids’ which belong to the cell cycle specific drugs mainly damage S and P phases of the cell cycles respectively. Antitumuor antibiotics primarily affect G1 and S stages (Figure 1). Figure 1. Schematic representation of the phases at which various classes of anticancer drugs act on the cell cycle (Altinok, Francis & Goldbeter 2007). Chemotherapeutic drugs mainly affecting S phase are the antimetaolites. Analogues of DNA building blocks (i.e. nucleic acids) in these S phase-specific drugs intervene in DNA synthesis process and blocks steps in nucleotide formation process. Antagonists of purine (Mercaptopurine), pyrimidine (5 FU), adenosine (Cladribine) and folate (Methotrexate) are some examples for antimetabolic chemotherapy drugs that block cell growth through affecting DNA synthesis. Structurally they look similar to the building blocks of DNA molecules but actually they mimic and trick the dividing cells which result in the alteration of enzyme functions needed for protein synthesis and cellular metabolism that ultimately lead to cell death (Bielas et al. 2009). 5FU in combination with leucovirin prevents tumor lapse and improve the survival of patients with high – risk colon cancer (O’Connell et al. 1997) by inducing carcinoma cell death up to 60% (Backus et al. 2000). This drug activates metabolites which damage DNA and RNA metabolism by activating ATR and ATM dependent checkpoint signaling pathways (Huehls et al. 2011). A new class of antimetabolites i.e. pyridine thioglycosides, that arrest cell cycle at S phase was identified by Elgemeie et al. (2010). Mutations in the MSH2 gene cause many tumourigenic conditions including colon cancer (Martin et al. 2009). Methotrexate, which specifically effect S phase, influence these mutations to control the tumour. In general, S phase-specific antimetabolites like 6-mercaptopurine and 6-thioguanine are effective immunosuppressants and successfully treat inflammatory diseases (Karran 2006). Chemotherapeutic drugs of plant alkaloids (derivatives of plants) are active throughout the cell cycle but more specifically they attack M and sometimes S phases of the cell cycle. These anticancer agents bind to tubulin protein which is required to make the spindle during metaphase and thus known as ‘micro tubule agents’. Mitotic spindle formation is hampered with these drugs and hence the cell cannot continue division. Vinca alkaloids (Vincristine, Vinblastine, Vindesine, Vinorelbine) and Taxanes (Paclitaxel, Docetxel) belong to this category and they are used to control leaukamia and breast tumours (Alli et al. 2002). Sensitivity to such antimicrotubule drugs are mediated through regulating microtubule associated protein 4 (MAP4) and inducing p53 (tumour suppressor gene encoded by TP53) by DNA damaging agents can influence anti microtubule drugs through regulating MAP4 expression (Zhang et al. 1999). p53 activates DNA repair proteins when DNA is damaged or it initiate apoptosis. Hence over 50% human cancers have a deletion or a mutation in this tumour suppressor gene (Hollestin 1991). Cited references: Alli E, Bash-Babula J, Yang J M & Hait W N 2002, ‘Effect of Stahmin on the sensitivity to antimicrotubule drugs in human breast cancer’, Cancer Research, Vol.62, pp. 6864 Altinok A, Francis L & Goldbeter A 2007, ‘A cell cycle automation needed for probing circadian patterns of anticancer drug delivery’, Advanced drug delivery reviews, Vol.59, pp. 1036 – 1053. Backus H H, Pinedo H M, Wouters D, Kuiper C M, Jansen G, van Groeningen C J, Peters G J 2000, ‘Differences in the induction of DNA damage, cell cycle arrest, and cell death by 5-fluorouracil and antifolates’, Oncology Research, Vol.12, Issue 5, pp. 231-239. Bielas J H, Schmitt M W, Icreverzi A, Ericson N G & Loeb L A 2009, ‘Molecularly Evolved Thymidylate Synthase Inhibits 5-Fluorodeoxyuridine Toxicity in Human Hematopoietic Cells’, Humane Gene Therapy, Vol. 20 Issue 12, pp. 1703 – 1707. Collins K, Jacks T & Pavletich N P 1997, ‘The cell cycle and?cancer’, PNAS, Vol. 74, No.7, pp. 2776 – 2778. Eidukevicius R, Characiejus D, Janavicius R, Kazlauskaite N, Pasukoniene V, Mauricas M & Den Otter W 2005, ‘A method to estimate cell cycle time and growth fraction using bromodeoxyuridine-flow cytometry data from a single sample’ BMC Cancer, Vol. 5, 122. Elgemeie GH, Mahdy EM, Elgawish MA, Ahmed MM, Shousha WG, Eldin ME 2010, ‘A new class of antimetabolites: pyridine thioglycosides as potential anticancer agents’, Z Naturforsch C , Vol.65(9-10), pp. 577-87. Hartwell L H & Kastan M B 1994, ‘Cell cycle control and cancer’, Science, Vol. 266 (5192), pp. 1821 – 1828. Hollstein M, Sidransky D, Vogelstein B, Harris CC 1991, ‘p53 mutations in human cancers’. Science, Vol. 253(5015), pp. 49–53. Huehls A M, Wagner J M, Huntoon C J, Geng L, Erlichman C, Patel A G, Kaufmann S H & Karnitz L M 2011, ‘ Poly(ADP-Ribose) Polymerase Inhibition Synergizes with 5-Fluorodeoxyuridine but not 5-Fluorouracil in Ovarian Cancer Cells’, Cancer Research, Vol. 71, 4944. Karran P 2006, ‘Thiopurines, DNA damage, DNA repair and therapy-related cancer’, British Medical Bulletin, Volume79-80, Issue1, pp. 153-170. Lewin B 1990, ‘Genes 1V’, Oxford University Press, New York. Martin SA, McCarthy A, Barber LJ, Burgess DJ, Parry S, Lord CJ, Ashworth A 2009, ‘Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2’, EMBO Molecular Medicine, Vol. 1 (6-7), pp. 323-337. Muller M, Wilderll S, Bannasch D, Israelill, Lehlbach K, Li-Weber M, Friedman S L, Galle P R, Stremmel W, Orenll M & Krammer P H 1998, ‘p53 Activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs’, Journal of Experimental Medicine, Vol. 188 No. 11, pp. 2033 – 2045 Nishida H, Tatewaki N, Nakajima Y, Magara T, Ko K M, Hamamori Y & Konishi T 2009, ‘Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response’, Nucleic Acids Research, Vol. 37 Issue 17, pp. 5678 - 5689. O'Connell M J, Mailliard J A, Kahn M J, Macdonald J S, Haller D G, Mayer D J & Wieand H S 1997, ‘Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer’, Journal of Clinical Oncology, Vol. 15, pp. 246-250. Zhang C C, Yang J M, Bash-Babula J, White E, Murphy M, Levine AJ & Hait WN 1999, ‘DNA damage increases sensitivity to vinca alkaloids and decreases sensitivity to taxanes through p53-dependent repression of microtubule-associated protein 4’, Cancer Research, Vol. 59 Issue 15, pp. 3663 – 3670. Read More