Classification of anticancer agents
Classes
• Alkylating agents
• Anti metabolites
• Plant derived agents & derivatives
• Antibiotics
• Enzymes
• Hormones & analogues
• Targeted Therapies
• Miscellaneous
ALK
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Classification of anticancer agents
Classes
• Alkylating agents
• Anti metabolites
• Plant derived agents & derivatives
• Antibiotics
• Enzymes
• Hormones & analogues
• Targeted Therapies
• Miscellaneous
ALKYLATING AGENTS
Sub-classes
• Nitrogen mustards e.g. mechlorethamine synomyn nitrogen mustard, cyclophosphamide, ifosfamide , trofosfamide, melphalan (L-sarcolysine), chlorambucil, Uramustine (uracil mustard), bendamustine (mechlorethamine derivative)
• Alkyl sulphonates – Busulfan
• Nitrosoureas – Carmustine (BCNU) Lomustine (CCNU)
semustine (methyl CCNU) – Streptozocin (streptozotocin)
• Triazenes – Dacarbazine ( or DTIC)
• Ethyleneimines & methylmelamines– Triethylenemelamine (TEM) thiopeta (Triethylene thiophosphoramide) Hexamethylmelamine (HMM)
• Platinum containing complexes- Cisplatin,carboplatin, Oxaliplatin
General Mechanism of Action
• Effects of these compounds to some extent resembles those of X-ray radiation and for this reason, they are sometimes referred to as radiomimetics
• undergo strongly electrophilic chemical reactions through the formation of carbonium ion intermediates or formation of transition complexes with the target molecules
• Readily form covalent linkages (i.e. alkylation) with various nucleophilic cell constituents such as phosphates, amino, sulfhydryl, hydroxyl, carboxyl and imidazole groups.
General Mechanism of Action
• The main target for expression of cytotoxic effect is the DNA
• The 7 nitrogen atom of guanine is strongly nucleophillic and therefore particularly susceptible to the formation of a covalent bond with both monofunctional and bifunctional alkylators and is the main purine base that is affected.
• other atoms in the purine and pyrimidine bases of DNA e.g. the 1 or 3 nitrogens of adenine, the 3-nitrogen of cytosine, and the 6 – oxygen of guanine alkylated but to a lesser degree,
• phosphate atoms of the DNA chains and proteins associated with DNA can also be alkylated.
General Mechanism of Action
• Naturally, Guanine exists predominantly as the Keto tautomer in DNA
• readily forms bases pairs by hydrogen bonding with cytosine residues.
• 7 nitrogen alkylated to become a quartenary ammonium nitrogen
• becomes more acidic and the enol tautomer predominates.
• guanine then forms base pairs with thymine instead of cytosine
1. Miscoding may follow with the ultimate substitution of adenine thymine base pair for guanine-cytosine base pair.
2. Alkylation of the 7 nitrogen labializes the imidazole ring
– the ring opens while still remaining part of the DNA molecule
– or excision of guanine residue (guanine expelled) from the DNA chain,
– either effect leads to serious damage to the DNA molecule with the later case making the DNA molecule unstable and may break.
3. Bifunctional agents e.g. nitrogen mustard
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