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systemic therapy (Chemotherapy (mechanism of action (antibiotics…

- - - - interaction with DNA by forming covalent bonds with nucleic acid --> misreading of DNA code, cross-linking of DNA, single - strand breaks, double- strand breaks
        
        alkylation of RNA and proteins
    - - antifolates: disruption of folate- dependent metabolic processes essential for cell replication by inhibition of: dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, thymidylate synthase
        
        purine analogues, pirimidine analogues, adenosine analogues: interference with synthesis of DNA precursors
    - - anthracyclines:
        intercalation between DNA base pairs, inhibition of DNA topoisomerases I and II
        free radical formation
        
        bleomycin:
        intercalation of DNA at G-C and G-T sequences, resulting in spontaneous oxidation and formation of free oxygen radicals that cause strand breakage
      - mitomycin C: alkylation and cross-linking of DNA, lipid peroxydation
        
        actinomycin D: DNA intercalation, single strand breaks formation, free radical formation
    - - topo I inhibitors:
        inhibition of topo I, interruption of the elongation phase of DNA replication
        
        topo II inhibitors
        stabilisation of DNA-topo complex, leading to inability to synthesize DNA and G1 block
    - - Vinca alkaloids:
        tubulin binding, blockage of microtubule polimerization,
        impaired mitotic spindle formation
        
        taxanes:
        promotion of microtubule assembly and stability
        M phase block, induction of apoptosis
  - - - decreased drug accumulation: decreased influx, increase efflux, altered intracellular trafficking of drug
        
        decreased drug activation
        
        increased inactivation of drug or toxic metabolite
        
        increased repair of drug-induced damage to DNA, proteins or membranes
        
        increase in an alternative metabolic pathway bypassing the target mechanism
        
        altered drug targets
        
        altered co-factor or metabolite level
        
        altered gene expression
        DNA mutation, amplification or deletion
        altered transcription, post transcription processing or translation
        altered stability of macromolecules
    - - pharmacologic and anatomic drug barriers
        
        host-drug interactions:
        decrease or increase drug activation by normal tissue
        relative increase in drug sensitivity of normal tissues
        
        host-tumor interactions
    - - kinetic resistance of cells in G0
        
        pharmacologic resistance- inability to achieve sufficient drug concentrations
- - - - possibility to assess effect of treatment in vivo
        
        early introduction of systemic therapy (prevention of development of chemoresistance)
        
        undisturbed blood supply
        
        prevention of tumor seeding during surgery
        
        enabling of decreasing the extent of surgery
        
        lack of interfering toxicities form other treatments
      - -ve
        
        delay in local treatment (risk of progression)
        
        increased risk of local treatment complications
    - - +no delay of any treatment modality
        +synergistic effect of various modalities
        -increased toxicity
        -need to modify doses of individual treatment modalities
    - - +no delay in local treatment
        +higher sensitivity of microscopic tumor foci
        -lack of possibility to assess efficacy of treatment
        -delayed start of systemic treatment (possibility of develppment of resistance)
        -impaired blood supply (and drug penetration)