Chemotherapy Agents

Question 1

Notes on alkylating agents

Answer 1

• E.g. cyclophosphamide, chlorambucil, melphalan, busulfan, dacarbazine
• Interfere with DNA synthesis by cross-linking DNA strands causing strand breaks
• Side effects:
  
  • Myelosuppression
  • Infertility
  • Secondary malignancy (AML)
  • Haemorrhagic cystitis with cyclophosphamide → prevent with hydration and MESNA
    
    • Acrolein is the toxic metabolite responsible for bladder toxicity
  • Interstitial pneumonitis and pulmonary fibrosis with long-term busulfan and cyclophosphamide
  • Hepatic enzyme induction with repeated dose cyclophosphamide
  • Cyclophosphamide → severe cardiotoxicity if large dose over short period (usually seen in setting of BMT)

Question 2

Notes on platinum chemotherapy agents

Answer 2

• E.g. cisplatin, carboplatin, oxaliplatin
• Causes cross-links of DNA (Intrastrand 70%, interstrand 20%)
• Side effects:
  
  • Cisplatin:
    
    • Severe nausea and vomiting
    • Peripheral neuropathy with cumulative dose
    • Nephrotoxic (90% renally excreted)
  • Carboplatin
    
    • Less nephro, neuro, emetogenic that cisplatin
    • Myelosuppression main toxicity
  • Oxaliplatin
    
    • Peripheral neuropathy

Question 3

Notes on antimetabolites → folate antagonists used as chemotherapy

Answer 3

• Methotrexate → leukaemia, breast, head, neck lymphomas, bladder ca
  
  • Binds to dihydrofolate reductase to prevent conversion of folic acid to folinic acid
• Pemetrexed → mesothelioma, second therapy for advanced NSCLCs
  
  • Multi-targeted anti-folate. Inhibits DHFR and GARF
• Nephrotoxic
• Rescue therapy with folinic acid
• Vitamin B12 and folate reduce toxicity

Question 4

Notes on antimetabolites → pyrimidine antagonists used as chemotherapy

Answer 4

• E.g. 5-fluorouracil, capecitabine
• Used in breast, CRC, UGI, head, neck, carcinoids
• Inhibits pyrimidine synthesis by blocking the enzyme thymidylate synthase
• Side effects:
  
  • Skin → plantar-palmar dermatitis
  • Acute neurological syndroe
  • 5FU: Cardiac ischaemia secondary to coronary spasm
• Radiation sensitiser

From CRC lecture:

• Inhibit thymidine synthesis. Metabolites incoorporated into DNA that → apoptosies
• Toxicities → mucositis, diarrhoea, nausea/vomiting, caronary artery vasospasm and nyelosuppression
• Metabolised by dihydropyrimidine dehydrogenase → deficiency of this enzyme → 2-8% population → myelosuppresion and horrible mucositis

Question 5

Notes on anti-metabolite arabinosides used as chemotherapy agents

Answer 5

• Cytosine arabinoside (AML), Gemcitabine (lung, breast, pancreas, bladder), fludarabine (B-Cell CLL)
• Inhibits DNA synthesis by inhibiting DNA polymerase

Question 6

Notes on anti-metabolites purine antagonists used as chemotherapy agents

Answer 6

• 6MP, 6-thioguanine → used in acute leukaemia

Question 7

Notes on DNA repair inhibitors - epipodopyllotoxins used chemotherapy agents

Answer 7

• Irinotecan, topotecan → lung, ovary, colon, cervix → inhibits topoisomerase I
• Etoposide → inhibits topoisomerase II
• Diarrhoea - major dose limiting toxicity of irinotecan, also myelosuppression
  
  • Gilbert syndrome increases risk of irinotecan toxicity (UAT181 deficiency) → can be fatal, presents as myelosuppression

Question 8

Notes on DNA repair inhibitors → anthracyclines used as chemotherapy agents

Answer 8

• Doxorbicin (inhibits topoisomerase II), epirubicin, bleomycin (promote cleavage of DNA and RNA), mitoxantrone
• Used in breast bladder, lung, gynae, prostate, ovary, sarcomas, thyroid, lymphoma, leukaemia
• Side effects:
  
  • Cardiotoxicity - dose related
  • Infertility
  • Pulmonary toxicity - no good screening for early detection of this (and false positives may lead to under-treatment)
  • Myelosuppression
  • Extravasation
• Overexpression of MDR 1 gene encoding p-glycoprotein is responsible for chemo resistance
• Binding to heparin will reduce half life of doxorubicin.
• Radiosensitiser - also daunorubicin may cause a radiation recall reaction presenting as a rash over an area that previously received radiotherapy

Question 9

Notes anti-tubulin → vinca alkaloids used as chemotherapy agents

Answer 9

• Vincristine, vinblastine, vinorelbine
• Inhibits microtubule formation by binding to tubulin
• Neurotoxic
• Never give vincristine intrathecally

Question 10

Notes on anti-tubulin → taxanes used as chemotherapy agents

Answer 10

• E.g. paclitaxel, docetaxel
• Used in ovarian, breast, lung
• Prevent microtubule formation by binding to tubulin dimers
• Side effects:
  
  • Neurotoxicity
  • Infertility
  • Hypersensitivity reactions
• Dose reduce in liver impairment

Question 11

Classes of DNA damaging chemotherapy agents

Answer 11

1. Alkylating agents
2. Platinum compounds

Question 12

Classes of anti-metabolites used in chemotherapy agents

Answer 12

1. Folic acid antagonist
2. Pyrimidine atangonist
3. Arabinoside (gemcitabine, fludarabine)
4. Purine antagonist - 6MP

Question 13

Classes of DNA repair inhibitors used as chemotherapy agents

Answer 13

1. Epipodophyllotoxins e.g. irinotecan, etoposide
2. Anthracyclines

Question 14

Classes of anti-tubulin chemotherapy agents

Answer 14

1. Vinca alkaloids
2. Taxanes

Question 15

Chemotherapy agents that cause alopecia

Answer 15

• 5-FU
• Antracyclines
• Irinotecan
• Paclitaxel

Question 16

Chemotherapy agents that cause vomiting

Answer 16

• Cyclophosphamide
• Cisplatin (severe)
• Irinotecan

Question 17

Chemotherapy agents that cause myelosuppression

Answer 17

• Anthracyclines
• Cyclophosphamide
• Carboplatin
• Etoposide

Question 18

Chemotherapy agents that cause mucositis

Answer 18

• 5-FU
• Anthracyclines