W8 Cancer Pharmacology (MAH) Flashcards
What are the goals of chemotherapy? (3)
Cure cancer- with high proliferation rates, such as lymphoma, testicular cancer, NHL, ALL, Wilm’s tumour.
Control cancer- Prolong remission, Decrease rate of relapse
Palliative therapy- Relieve symptoms, Improve quality of life
- Eradicate macroscopic disease
e.g. lymphoma, teratoma. - Eradicate microscopic disease
e.g. breast, bowel, lung - Facilitate radical treatments
e.g. bladder, breast, oesophageal - Control disease
What is the definition of tumour suppressor genes?
- TUMOUR SUPPRESSOR GENES: encodes a protein that acts to regulate cell division, keeping it in check. When a tumour suppressor gene e.g. p53 is inactivated by a mutation, the protein it encodes is not produced or does not function properly»_space;> uncontrolled cell division.
- Tumour suppressor genes are present in all cells in our body
What is the definition of oncogenes?
An oncogene is a mutated gene that has the potential to cause cancer. Before an
oncogene becomes mutated, it is called a proto-oncogene, and it plays a role in regulating normal cell division. Cancer can arise when a proto-oncogene is mutated, changing it into an oncogene and causing the cell to divide and multiply uncontrollably
* Example - HER2 gene that makes HER2 protein. This protein helps control healthy breast cell division and growth. Extra copies of this gene may lead to an excess of HER2 protein, which causes cells to grow more quickly
What are the 6 cancer treatment options?
- Surgery
- Radiation therapy
- Chemotherapy
- Endocrine therapy
- Biological therapy
- Immunotherapy
What is antimicrobial chem vs cancer chemo?
Antimicrobial: Cytotoxic agents that
kill microorganisms without having any
effect on host cell
Cancer: deally cytotoxic agents
that kill cancer cells without having any
effect on host cells: This is far from reality at this moment
Name some traditional Chemotherapeutic Agents? (5)
- Alkylating agents e.g. nitrogen mustards, cisplatin [ARREST CELL CYCLE IN G1]
- Anti-metabolites [DISRUPTS DNA/RNA METABOLISM INTERRUPTING S-Phase]
- Mitosis inhibitors e.g. anti-tumour antibiotics anthracyclines inhibits topoisomerase II /
Helicase / induce ROS [DISRUPTS MITOSIS] - Topoisomerase Inhibitors [DISRUPTS MITOSIS]
- Anti-microtubule agents [DISRUPTS MITOSIS]
Route of administration of ca drugs?
- Oral
- Intravenous
- Intrathecally into the cerebrospinal fluid via spinal cord e.g. MTX for CNS leukaemia
- check drug to avoid fatal errors
- Subcutaneous
- Intrapleural
- Intraperitoneal e.g. cisplatin in ovarian cancer
- Intraarterial e.g. liver
- Into the bladder intravesicular instilling
Pharmacokinetic considerations?
- interindividual pharmacokinetic variability
»>unpredictable clinical effects - Genetic polymorphisms in drug-disposition pathways
SOLUTION:
* Tailoring doses of anticancer drugs to the individual patient
* Age
* BMI
* Health
* Stage of disease
* Individualised dosing strategies are promising, although few are used in routine clinical practice
General adverse effects of cytotoxic drugs?
- Nausea and vomiting
- Bone marrow suppression: bleeding, infection
- Gut epithelium and other mucosal surfaces: diarrhoea, mouth ulcers
- Pain
- Hair follicles: alopecia
- Germ cells and reproduction: sterility, teratogenesis
- Delayed wound healing
- Local toxicity
- Fluid retention
- Hyperuricemia
- Specific organ damage
- Second malignancies
- bowel obstruction
- Urothelial toxicity commonly manifests as haemorrhagic cystitis, and is specific to the use of cyclophosphamide and ifosfamide and caused by their metabolite: acrolein
How to overcome side effects
How to overcome resistance to chemotherapeutic agents?
A basic principle of anti-cancer therapy is
that chemotherapy is given in courses,
interspersed with gaps of varying duration
to allow recovery of normal cells
Shotgun approach – combination therapy
* Target different aspects of the cell cycle,
hormones
* Apoptotic pathway defects
* Enhance DNA repair mechanisms
* Altered membrane transport (e.G.
Upregulation of ABC transporters)
* Enhanced enzymatic deactivation
* Tumour suppressor genes
* Protooncogenes
Pharmaceutical Management of side effects
Nausea and vomiting:
- Common and can be severe
- May be immediate (within 1-5 hours), or delayed for several days
The most effective drugs: - 5-HT3 receptors antagonists: ondansetron
- D2-dopamine antagonists: metoclopramide
They may be used in combination with: - Benzodiazepine (anxiety)
- Dexamethasone
Combinations are often more effective than a single drug e.G. - Benzodiazepine plus dexamethasone plus: a 5-ht3 blocker (ondansetron) or d2- receptor blocker (metoclopramide)
Pharmaceutical Management of side effects
Bone marrow suppression
- Single most important dose-limiting factor with cytotoxics associated with the twin danger of:
➢Infection: often opportunistic by gram-negative bacteria e.G. From the gut.OR: virus
(H.Zoster), fungus (candida), protozoa (pneumocystis).
➢Bleeding: due to thrombocytopenia
Bone marrow suppression could be: - Deliberate e.g. In treatment of leukaemia
- Toxicity:
➢Rapid e.g. Nitrogen mustard, cyclophosphamide, MTX, vinblastine, ….
➢Delayed e.g. Nitrosureas, melphalan (for 6-12 weeks) - All cytotoxic drugs cause significant bone marrow suppression except bleomycin and vincristine.
Pharmaceutical Management of side effects
Hyperuricemia - an abnormally high level of uric acid in the blood, associated especially with gout.
- May occur with lymphoma and leukaemia
- Can be worsened by chemotherapy
- May cause acute renal failure
- Allopurinol can be started 24 hours before treating such tumours; patients should be well hydrated
- With allopurinol, the dose of mercaptopurine and azathioprine should be reduced
Pharmaceutical Management of side effects:
Alopecia (Reversible hair loss)
The most frequent offenders are: adriamycin and cyclo-phosphamide
Fertility
Females: do not usually have any long-term effect on fertility although frequently stop
menstruation
Males: profound reduction in sperm count particularly with alkylating agents
3. No conception should be attempted when one partner is being treated. The safe period is unknown, probably 4-6 months
Common drug interactions:
Methotrexate and salicylate
MTX highly protein bound»_space;> displaced by aspirin»_space;> increased risk of adverse effects due to increase in free MTX exerting its effects
SIDE EFFECTS: nausea, vomiting, diarrhea, sore throat, chills, fever, rash, unusual bruising or
bleeding, pale skin, dark urine, swelling of the extremities, or shortness of breath.
MTX patients are advised not to take aspirin
