DNA Damaging Drugs

Abstract

The classical anti-cancer agents comprise cytotoxic compounds. Mostly, these drugs act by exerting DNA damage. In essence, there are two major response phenotypes available to a cell upon DNA damage, such as a chemotherapeutic drug action, -to arrest the cell cycle and repair the damage, -to initiate a pathway to apoptosis (programmed cell death).In either scenario, the uncontrolled growth of the tumor cells is curtailed. The major limitation of the cytotoxic anti-cancer drugs is the tumor non-specific action, and the suppression of all rapidly dividing cells 1 . Alkylating AgentsAlkylating agents 2 are electrophilic and bind covalently to electron-rich functional groups of various target molecules via first-order or second-order nucleophilic substitutions (nucleophiles are electron-rich molecules or ions, such as OH − , H 2 O, halogenides, alcohols, thiols and amines). The first order reactants include aromatic and aliphatic nitrogen and sulfur mustards. Second order reactants include ethylene 1 Because the desired drug actions (damage to rapidly proliferating cancer cells) and the adverse effects (damage to rapidly proliferating healthy cells) are identical in targets and mechanisms, they are not separable. 2 Alkyl designates a functional group (a "side chain") that consists solely of single-bonded carbon and hydrogen atoms. Alkylating anticancer agents attach alkyl groups to biomolecules. imines and epoxides, alkylmethane sulfonates of the busulfan (Myleran) type, and α-halogenated acids, ketones, and their derivatives.-For first-order reactions, the rate limiting step is the ionization of the alkylating agent to form a positively charged carbonium ion, which then rapidly reacts with water, or a negative center, or a nucleophilic center. Within DNA and RNA, the most reactive site is the N 7 position of guanine ( Fig. 2.1). In DNA, this is followed by N 3 of adenine, N 1 of adenine, N 1 of cytosine, and N 7 of adenine (Table 2.1). The rate limiting step of the reaction is the formation of positively charged cyclic immonium ions, whereas the rate of the reaction is essentially independent of the nature and concentration of the nucleophilic target being attacked. -For second order nucleophilic substitutions, both reactants interact to form a transition complex. No carbonium ion is formed. The rate of the reaction depends on both concentrations, with bond strengths, electron affinity, and accessibility of both reagents being important (Knock 1967).Alkylating agents exert cytotoxic effects by transferring alkyl groups to DNA, thereby damaging the DNA and interfering with DNA transcription and cell division. This class of drugs mainly works by three distinct mechanisms:-The attachment of alkyl groups to DNA bases prevents DNA synthesis and RNA transcription, and it results in the DNA being fragmented by repair enzymes in a process to replace the altered bases. -The two arms of mustard drugs can cross-link DNA strands. In this process, two bases are linked together. Bridges can be formed within a single molecule of...

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“…It works by binding inside cells to nucleophiles, such as DNA, RNA, and bases, to form adducts, which induce apoptosis [ 15 ]. Vomiting is the earliest GI symptom and is usually associated with a peak in the urinary metabolites of serotonin, suggesting a strong correlation between the release of serotonin with this agent and vomiting [ 16 ]. Oxaliplatin, on the other hand, has a large number of GI side effects: diarrhea and nausea, vomiting, stomatitis, dry mouth, melaena, bleeding, proctitis, and tenesmus.…”

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“…Klastojenik ve anöjenik etki, iğ ipliklerinin oluşumundaki bir inhibisyonundan, DNA bazlarının alkillenmesinden ya da her iki olaydan da kaynaklanabilir. Alkilleyici ajanlar DNA bazlarına alkil grupları bağlayarak, nükleotidlerde çapraz bağlar oluşturarak DNA hasarına yol açabilirler [42,43]. Ayrıca klastojen veya anöjenlere maruz kalınması halinde, hücre bölünmesinde görev yapan genetik kontrol noktalarında ve/veya DNA tamir genlerinde meydana gelen hatalardan dolayı da MN frekansı artabilir [44,45].…”

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