Endocrine Therapy

• Endocrine Therapy

  • Beatson 1896 ovary removal and breast cancer
  • Tumours derived from hormone-sensitive tissue may be hormone dependent
  • Their growth inhibited by drugs that:
  • (a) oppose relevant hormonal action
  • (b) inhibit the synthesis of relevant hormones
• hormone type: oestrogens

  • e.g.: diethylstilbestrol (blocks effect of androgens)
  • usual adult dose: 1-5mg 3 times day orally
  • clinical use: prostate cancer
• hormone type: anti-oestrogens

  • e.g.: tamoxifen
  • usual adult dose: 20mg/day orally
  • clinical use: breast cancer
• hormone type: progesterones

  • e.g.: medroxy-progesterone
  • usual adult dose: 100-200mg/day orally
  • clinical use: endometrial cancers
• hormone type: GTRH agonist

  • e.g.: leuprolide (blocks release of androgens via decreasing LH and FSH)
  • usual adult dose: 1mg/day subcutaneous
  • clinical use: advanced breast cancer and prostate
• hormone type: anti-androgens

  • e.g.: flutamide
  • usual adult dose: 500mg/day orally
  • clinical use: testicular cancer
• GTRH = gonadotrophin releasing hormone
• Tamoxifen (Nolvadex)

  • Non-steroid. Competitive inhibitor of oestrogen
  • Has anti-oestrogen action on breast tissue but oestrogenic action on endometrium and bone
  • Binds oestrogen receptor in nucleus but little or no stimulation of transcription occurs
  • Increases TGF- β (which inhibits proliferation) 
• tamoxifen toxicity

  • Hot flashes
  • Nausea
  • Fluid retention
  • 3-4 fold increased risk of endometrial cancer (PM)
  • New analogues: Raloxifene but used to prevent osteoporosis in post-menopausal
• Arimidex

  • 13,000 die each year in UK of breast cancer despite use of Tamoxifen
  • Arimidex is an aromatase inhibitor, hence reduces eostrogen
  • For postmenopausal, early invasive tumour patients. Also used for ovarian cancer. 
  • Switching from standard therapy to Arimidex reduced death by 29%, re-occurance fell by 26% 
• challenges of cancer treatment - drug resistance

  • decreased drug uptake
  • increased drug effect (MDR)
  • insufficient drug activation
  • increase repair enzymes
  • enzyme amplification
• pharmaceutical challenges in cancer chemotherapy - drug toxicity

  • Inflammation of oral mucosa
  • Alopecia
  • Bone marrow suppression (neutropenia, thrombocytopenia, anaemias
  • GI tox (nausea, vomiting diarrhoea)
  • Neurotoxicity (confusion/headaches
• pharmaceutical challenges in cancer chemotherapy - drug resistance (inherent or acquired)

  • Decreased accumulation of drug
  • Insufficient drug activation
  • Decrease drug uptake
  • Increase in inactivation
  • Enhanced DNA repair
  • Alteration of drug targets & pathways
  • Change in tumour suppressors