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Alkylating Agents

  1. Nitrogen mustards
    1. Meclorethmine              
    2. Melphlan              
    3. Chlorambucil        
    4. Cyclophosphamide                
    5. Ifosafamide          
    6. Gluphosphamide            
    7. Bendamustine
  2. Alkylsulfone
     
    a. Busalfan
  3. Nitrosourea
    1. Carmustine          
    2. Lomustine            
    3. Semustine
  4. Ethylenenemines
    1. Altreatamine                
    2. Mitomycin
  5. Miscellaneous
    1. Procarbazine                
    2. Dacarbazine 

Alkylating agents …General properties

  • Non-cell cycle specific
  1. Rapidly acting              
  2. Work better in large tumors          
  3. Apoptosis & necrosis
  4. Radiomimetic              
  5. Radiation recall                    
  6. Infertility/sterility occurs
  7. Nausea is MC side effect

MAO

  1. Form a covalent bond with (Gaunine-N-7) of DNA
  2. Produce irreversible damage to DNA
  3. Resistance occurs due to increase in DNA repair (e.g. increased expression of glutathione transferase)   

Individual Drugs

  1. Meclorethmine
    1. Oldest anticancer drug
    2. Rapidly drug
    3. Vesicant
    4. Given as IV infusion (MOPP)
    5. Use: Hodgkin’s lymphoma
    6. S/e=bone marrow depression, pulmonary fibrosis can occur    
  2. Chlorambucil
    1. Slowly acting alkylating agent
    2. DOC
      1. Waldenstrom macrogammagobinemia
      2. CLL (Fludarabine is preferred)
  3. Melphlan
    1. Slowly acting
    2. Does not cause vomiting
    3. Eliminated by bile
    4. DOC
    5. Multiple myeloma
    6. S/e=bone marrow depression, GI Upset (MC)  
Extra edge

Multiple myeloma
(refractory)

  • Thalidomide (TNF-alpha blocker)
  • Borteozombin and lenodilamide combination (Advanced cases)
  1. Cyclophosphamide
    1. MC used alkylating agent
    2. Prodrug; aldophosphamide(Active), acrolein (Toxic)
    3. Metabolized by CYP 3A4 (Inhibited by chloramphenicol) 
    4. Uses
      1. Wegner’s granulomatosis
      2. CHOP regimen (not in MOPP)
      3. Small cell lung cancer          
      4. Neuroblastoma  
      5. Nesidioblastoma          
      6. Choriocarcinoma          
      7. Ovarian Ca          
      8. Testicular Ca (Not in uterine Ca-MPA)

S/E

  • MC
  1. Hemorrhagic necrosis of bladder
    1. Manifests as hematuria
    2. Prevention–adequate hydration
    3. Treatment-MESNA (SH donating agent)
    4. Oral/intravesical/intravenous
    5. IV is best route   
  2. Cardiotoxic
  3. Pulmonary fibrosis
  4. Infertility
  5. Sterility
  6. Bone marrow depression (Dose limiting)  

5. Ifosafamide

  1. Structural analogue of cyclophosphamide
  2. Also cause necrosis of bladder
  3. Cause more alopecia and neurotoxicity
  4. Form one inactive metabolite i.e. chloracetaldehyde
  5. Metabolized by CYP3A4 enzyme of liver
  6. Use ,Ca Lung 

6. Gluphosphamide

  • Does not cause necrosis of bladder

7. Busulfan

  1. Rapidly acting                              
  2. Maximally myelotoxic  
  3. Orally given; eliminated by bile            
  4. Used in CML
  5. S/E
    1. Pulmonary fibrosis (More with bleomycin)            
    2. Bone marrow depression
    3. Hyperpigmentation                              
    4. Hyperuricemia (Tumor lysis-Rx-rasburicase) 

8. Mitomycin

  1. Dual drug Alkylating agent+ antitumor antibiotic
  2. Sensitizes hypoxic cells
  3. Radiomimetic
  4. Radiation recall
  5. Use
    1. Superficial Ca of Urinary Bladder
    2. Peritoneal tumor
    3. Laryngeotracheal stenosis
    4. Esophageal stenosis
    5. After corenal surgeries like LASIK 

Chemo-sensitizers

  1. Mitomycin
  2. Bleomycin
  3. Efoproxiral
    1. To be tested by DOPE test
    2. Allosteric modulator of Hb
  4. Tirapazemine (Antileukemia)
     
    i. Cloretazine is another new drug

9. Nitrosoureas

  1. Fastest, shortest acting
  2. Lipid soluble Enter BBB
  3. DOC Ca Brain
  4. S/E
    1. Pulmonary fibrosis
    2. Bone marrow depression
    3. Vesicant
    4. Cause delayed bone marrow suppression as well as sustained myelosuppression

10. Other drugs

  1. Flavipirdol  Promotes apoptosis
  2. Temozolamide

DOC

→ Glioblastoma multiforme

  1. Oral alkylating agent
  2. Given empty stomach
  3. Marked nausea and vomiting





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