Pharmacology – Oncology lecture 1 Flashcards
(37 cards)
Which genes are affected (1)? - The Hallmarks of cancer
-Enabling characteristics:
Genomic instability
Inflammation
- Emerging characteristics:
Energy metabolism
Evade immune destruction
-Non-tumour cells:
Role of the microenvironment
Two Key Headlines
- Cancer progresses from early to late stages. Its easier to treat early stage tumours: early detection is beneficial
- Metastasis is generally associated with a poor outcome
-Plasia:
– Anaplasia: de-differentation of a cell
– Dysplasia: altered organization of a tissue
– Hyperplasia: increased # cells in a tissue
Tumour:
– an abnormal growth
– neoplasm
Benign
– a non-invasive growth, usually encapsulated, not invasive
– names often ends with “-oma” (but not -carcinoma) eg adenoma = benign
– usually not fatal
Malignant:
– an invasive cancerous growth
– often fatal if untreated
– carcinoma – malignant tumour of epithelial cell origin (most common)
– sarcoma - malignant tumour of connective tissue or muscle
Invasion:
migration into local tissue through surrounding membrane
Metastasis:
migration (through blood or lymph vessels) to and growth at a distant site
Disease staging:
– assessment of how far the tumour has spread; the “extent” of the disease;
– different cancers have different criteria
Tumour grade
– degree of de-differentation of a cells in a tumour
– assigned by histological examination
Cytotoxic
something that kills cells
Cytostatic
something that inhibits cell proliferation
Types of treatment
• “Chemotherapy”
– usually cytotoxic therapy
– drugs which interfere with fundamental cellular processes
– depend on fact that cancer cells are proliferating, many other cells are not
– drug targets are involved in proliferation (particularly DNA)
– Often severe ADR, often associated with effects on proliferating cells
– Key issues: therapeutic window (ADR), drug resistance
• Hormone therapy
– where cancers are dependant on a particular hormone for growth
– eg breast, prostate cancers
– Key issue: cancer may become “hormone independent”
• “Targeted therapies” & biological therapy
– “target” the underlying cause or pathway activated by it
– may be cytotoxic or cytostatic
– Key issues: efficacy, patient selection, drug-resistance, cost
• Radiotherapy
– irradiation of patient or ingestion of radionuclide
• Palliative care
Chemotherapy generalizations
ADR
• Tissues with rapidly proliferating cells are affected:
– GI tract mucosa
» Diarrhoea
» nausea & vomiting
» Oral mucositis with some drugs
– Hair follicles
» Alopecia
– Bone marrow – myelosuppression see diagram
» neutrophils are most susceptible →neutropenia
» anaemia & thrombocytopenia
– Gonads
» male sterility; cryopreservation ?
– Fetus
» chemotherapy is usually teratogenic, contraindicated in pregnancy
• Individual drugs may have specific ADR in addition to this. These additional ADR are listed on the following slides
PK
• Several, but not all, chemotherapeutic drugs are administered i.v.
Cautions
• Do not give live vaccines to patients receiving chemotherapy
Dose
• Dose often expressed as mg /m2 – better correlation to effect
• 70kg man surface area ~1.73 m2
Alkylating agents
- Busulfan
- Carmustine (prodrug)
- Chlorambucil
- Cyclophosphamide (prodrug; activated by P450)
- Estramustine
- Ifosfamide
- Lomustine
- Melphalan
- Mitobronitol
- Thiotepa
- Treosulfan
Mechanism of action of alkylating agent
• Alkylation of nucleophilic sites on DNA – especially guanine N-7 and O-6
• Several alkylating agents have two leaving groups which allow base cross-linking
• Alternatively alkylation may result in excision of the base, ringopening, or incorrect base pairing
• If this results in a mutation in an essential gene in a cancer cell
→cell death
• BUT mutation in normal cell – can promote cancer !
Cyclophosphamide
• Example of an alkylating agent
• PK
– t1/2 ~ 5 hr;
– unusually long, alkylating agents tend to have short t1/2
– i.v or p.o.
– pro-drug- activated by hydroxylation by Cyp450
• Used for treatment of leukemia, lymphoma neuroblastoma, ovarian cancer, retinoblastoma, breast
cancer
Cytotoxic antibiotics: Anthracyclins
• Anthracyclins
– Aclarubicin
– Daunorubicin
– Doxorubicin
– Epirubicin
– Idarubicin
• Interchelate between DNA strands & inhibiting re-ligation of strands by topoisomerase II
• Risk of cardiac toxicity with these drugs esp. doxorubicin by generating free radicals
• Anthracyclines can colour urine
• Caution: anthracyclins with trastuzumab – cardiac toxicity likely
TOPOISOMERASE
- Topoisomerase regulate DNA supercoiling
- allow one strand to pass though another during replication
- Topoisomerase I cleaves and rejoins single strands
- Topoisomerase II cleaves and rejoins both
Cytotoxic antibiotics:Camptothecins, etoposide, bleomycin
Camptothecins • Camptothecins – Stabilize DNA:topoisomerase I complex – prevents topoisomerase I repairing the break • Camptothecins: – irinotecan – topotecan
Etoposide
• Stabilize DNA:topoisomerase II complex
• prevents topoisomerase II repairing the break
Bleomycin
• Glycopeptide that chelate Fe2+
• cleaves DNA strands
Anti-metabolites
- Fluorouracil (“5FU”)
- Capecitabine (5FU prodrug that is available po)
- Pemetrexed
- Gemcitabine
- Cytarabine
- Fludarabine
- Cladribine
- Raltitrexed
- Thioguanine
- Mercaptopurine
- Azathioprine (mercaptopurine pro-drug)
- Methotrexate
Azathioprine & mercaptopurine
• Azathioprine is pro-drug of mercaptopurine
– allopurinol inhibits metabolism of mercaptopurine
• Indications
– cancer, transplant rejection, rheumatoid arthritis, myasthenia gravis
• Cautions
– reduce dose in case of hepatic or renal impairment
– Do not give live vaccines while using this drug (immunosuppresant)
• ADR
– 5% of patients require dose reduction due to myelosuppression – risk of infection. Some patients are slow metabolizers – risk is greater
• Interactions
– increased myelosuppresion if used at the same time as antibiotics that inhibit folate metabolism (trimethoprim, co-trimoxazole)
Methotrexate: “anti-folate ”
• Indications
– apart from cancer also used to treat psoriasis and rheumatoid arthritis (once a week only)
• Caution
– avoid in renal impairment, hepatic insufficiency
– avoid in patients with ascites or pleural effusion pleural effusion – drug accumulates
• PK
– renal elimination unchanged – glomerular filtration & transport
– Some biliary excretion
– administered p.o, i.v, i.m, i.t
• ADR
– as other chemotherapy
– pulmonary toxicity
– long term treatment can cause liver cirrhosis
• Interactions
– Avoid with Aspirin and NSAIDS - inhibit excretion. Advise patient accordingly!
– penicillin also inhibit renal excretion of methotrexate into renal tubule - reduce dose
– do not use with other antifolate antibiotics (trimethoprim, co-trioxazole)
Purines and Pyrimidines incorporated into DNA
Impaired replication/transcription
• Thioguanine is phosphorylated to thiodGTP and is incorporated into DNA and interferes with transcription and replication
• Also interferes with guanine nucleotide synthesis
Chain termination
• Fludarabine (purine) and Cytarabine (deoxycytidine analogue) incorporated into DNA and RNA causing chain termination
• Gemcitabine (also deoxycytidine analogue) inhibits ribonucleotide reductase as well as being incorporated into DNA and causing chain termination
• Cladribine incorporated into DNA and causes strand breaks
Altered expression
• 5-Azacytidine (deoxycytidine analogue) incorporated into DNA put not methylated, alters gene expression (→differentiation)
