Chemotherapy

---
config:
  layout: dagre
---
graph TD
	subgraph A [Antimetabolites]
  K[6-Mercaptopurine 
	  6-Thioguanine 
	  Methotrexate --> DHFR]:::drug
  end 
  A--xB  
   
  O[5-Fluorouracil
  Cytarabine
  Gemcitabine]:::drug---xE
  
  B[Purine Synthesis]:::main
  C[Pyrimidine Synthesis]:::main
  B==> D[Ribonucleotides]:::main
  C==> D
  D==> E[Deoxyribonucleotides]:::main
  E==> F[DNA]:::main
  F==> G[RNA]:::main
  G==> H[Proteins]:::main
  H==> I[Enzymes]:::main
  H==> J[Microtubules]:::main
	
	N[Hydroxyurea]:::drug--xE
  
   R[Alkylating agents
	  Alkylation -> alter Sx & Fx fo DNA via cross linking
	  ]:::drug---xF

    S[Antibiotics]:::drug --xF
    T[L-Asparaginase]:::drug --xH
		
		U[Vinca Alkaloids --> prevent polymerization
		 Taxens --> enhance polymerization]:::drug --xJ
    
    W[Etoposide
	    Topoisomerase II Inhibitor - DNA break]:::drug --xF
classDef main fill:#000000,stroke:#FFFFFF,stroke-width:4px,color:#fff,font-size:18pt,stroke-dasharray:
classDef drug fill:#C0DFA1,color:#000000

• Mechanism of action
• Alkylating agent
• Methylating DNA guanine bases → cross linking of DNA → inhibited DNA and cellular replication
• Which is different from methylation of histones which reduces gene expression
• Work better with MGMT methylation → reduce MGMT functioning
• MGMT promoter
• Cells that are deficient in MGMT have shown an increased sensitivity to TMZ → Patients with low MGMT expression (due to methylation of the promoter) benefit more from adjuvant TMZ.
• MGMT promoter status may predict pseudoprogression in >90% of patients with methylated glioblastoma.
• 60% probability of early true tumour progression was observed in unmethylated MGMT promoter tumours
• Although it can occur following RT alone, pseudoprogression is widely believed to be more frequent following concomitant RT-TMZ

• Dose
• Strupp protocol
• During radiotherapy: 75 mg per square metre of body-surface area per day, 7 days per week
• Post-radiotherapy (adjuvant): six cycles consisting of 150-200 mg per square metre for 5 days during each 28-day cycle

• Side effects:
• Constipation
• N/V
• Fatigue
• Headache
• Amenorrhoea
• Loss of appetite
• Pneumonia
• Leucopenia
• Low platelets

• Evidence
• Has provided some improvement in survival.

• Mechanism of Action
• Doxorubicin intercalate within DNA base pairs, causing breakage of DNA strands and inhibition of both DNA and RNA synthesis.
• Doxorubicin inhibits the enzyme topoisomerase II, causing DNA damage and induction of apoptosis.
• When combined with iron, doxorubicin also causes free radical-mediated oxidative damage to DNA, further limiting DNA synthesis.
• Iron chelators, such as dexrazoxane, may prevent free radical formation by limiting the binding of doxorubicin with iron

• Causes high frequency hearing loss

• BBB excludes many chemotherapeutic agents from the CNS
• This concept has been challenged.
• With a notable exception being a favorable response of oligodendrogliomas and gliomas with deficient MGMT

• Considerations regarding chemotherapeutic agents in relation to the BBB include:
• Some CNS tumors may partially disrupt the BBB, especially malignant gliomas
• Lipophilic agents (e.g. nitrosoureas) may cross the BBB more readily
• Selective intra-arterial (e.g. intracarotid or intervertebral) injection: produces higher local concentration of agents which increases penetration of the BBB, with lower associated systemic toxicities than would otherwise occur
• BBB may be iatrogenically disrupted (e.g. with mannitol) prior to administration of the agent
• BBB may be bypassed by intrathecal administration of agents via LP or ventricular access device, e.g. methotrexate for CNS lymphoma (p.729)
• Biodegradable polymer wafers containing the agent may be directly implanted