Week 10 Flashcards
Objectives of cancer treatment
Cure the patient (kill or remove all cancer cells)
Prolong patient survival (kill most cancer cells)
Palliate symptoms (kill some cancer cells)
Chemotherapy: clinical contexts
For advanced disease:
-where no other treatment exists
Adjuvant chemotherapy:
-systemic treatment following local radiotherapy or surgery
-to control microscopic metastases
Primary or neo-adjuvant chemotherapy:
-chemotherapy as initial therapy for locally advanced cancer
-to render it more amenable to subsequent surgery
-improve cosmesis/function
-to control micro metastasis
Principles of chemotherapy
Cell cycle
G0 G1: microtubule inhibitors, topoisomerase inhibitors, alkylating agents
S: anti-metabolites, topoisomerase inhibitors
G2: platinum analogues
M: micro tubule inhibitors
Cell cycle specific drugs
Acts on cells in cell cycle and inhibits cell growth at specific phases
More effective against tumours with higher percentage of cell that are replicating
Cell cycle non specific drugs
Acts on resting and cycling cells
Useful against tumours with low or high percentage of replicating cells
Chemotherapy
Assumptions made in the use of cytotoxic chemotherapy:
-tumour growth proceeds exponentially independent of growth homeostasis but:
—a proportion are non dividing cells
—growth fraction may vary as a function of tumour size
-each dose results in the same proportional log kill but:
—proportional kill may also relate to growth fraction
—tumours are heterogeneous, and large tumours may be more likely to contain drug resistance clones
-intensity of dose influences outcome:
—cytotoxic drugs are given at close to the maximum tolerated dose
-different drugs have different kill properties
Log-kill kinetics model
Every dose of chemo kills cells by fixed proportion
Between cancer cells can grow again
With time go down to zero cells, uncommon, mixed cell population
Tumour kinetics
Gompertzian growth curve
Not until high number of cells is it clinically detected
Below that it’s a clinically undetectable tumour
Above that graph plateaus- death
Dose intensity
Norton-Simon. Hypothesis
-delivering treatments at a greater rate (“dose density”) could optimise chemotherapy efficacy
—minimising the regrowth of cancer between doses of therapy
—increase the cumulative cell kill
—achieving greater clinical benefit
Dose reductions for toxicity can reduce chance of cure
Dose delays enable fast growing micro metastases to recover
Chemotherapy agents
Alkylating agents
Platinum agents
Antimetabolites
Topoisomerase inhibitors
Antimicrotubular agents
Other agents
Molecular targeted agents
Alkylating agents
Diverse group of anti cancer agents
Covalently transfer alkyl groups to DNA bases
-base alkylation- monofunctional DNA adducts, subsequent processing or repair of these lesions leads to single strand breaks in the DNA/mispairing of nucleotides
-two bases are linked together by an alkylating agent forming cross bridges. Cross linking prevents DNA from being separated for DNA synthesis or transcription
Limited cell cycle specificity- binds directly to DNA
Examples alkylating agents
Cyclophosphamide
Ifosfamide
Mephalan
Chlorambucil
Platinum agents
Discovered electric current delivered to bacterial culture via platinum electrodes led to inhibition of bacterial growth
Active compound found to be cisplatin
Bind covalently to purine DNA bases (N7 position)
Bifunctional intra strand crosslinks
Prevents DNA double strand from separating
Not S phase specific
Nephrotoxicity and resistance
Antimetabolites
Acts at level of DNA synthesis
Interfere with incorporation of nucleic acid bases
Purine or pyrimidine analogues:
-inhibits formation of normal nucleotides
-often inhibit enzymes essential for DNA and RNA synthesis
Prevent formation of reduced folate:
-essential for transfer of methyl groups in DNA synthesis
Usually S phase specific
Acts on cancer and normal cells that are dividing rapidly
-can cause significant bone marrow and GIT toxicity
No late carcinogenesis
-does not interact directly with DNA
Examples Antimetabolites
Purine Antimetabolites:
-fludarabine
-cladrabine
Pyrimidine Antimetabolites:
-5FU
-capecitabine
-cytosine arabinoside (ara-C)
-gemcitabine
Antifolates:
-methotrexate
Topoisomerase inhibitors
DNA topoisomerases: ubiquitous nuclear enzymes
Relax supercoiled double stranded DNA to allow DNA replication and RNA transcription
Topoisomerase I- single strand nicks
Topoisomerase II- double strand nicks
Swivelling of supercoiled DNA occurs at nicks followed by re-ligation to relive torsional strain
Topoisomerase I inhibitor
Bind to and stabilise the DNA-topoisomerase I adducts
Inhibits religation of DNA strands
Single strand breaks in DNA
Examples:
-camptothecin
-irinotecan
-topotecan
Topoisomerase II inhibitors
Forms a complex with topoisomerase II after cleavage of DNA
Inhibits religation of DNA strands
Single and double strand breaks in DNA
Examples:
-etoposide
-anthracyclines
Antimicrotubular agents
Prevent spindle formation
-essential for sorting and moving of chromosomes following replication at end of mitosis
Vinca alkaloids:
-vincristine
-vinblastine
-vinorelbine
Binds to tubulin, preventing polymerisation of microtubules
-inhibits cell cycle progression
Taxanes: paclitaxel, docetaxel
-binds to tubulin (different site to vinca alkaloids)
—prevents microtubular disassembly
-disrupts normal microtubule dynamics that’s required for cell divisions
Combination chemotherapy
Provides maximum cell kill within the range of toxicity that can be tolerated for each drug
Provides a broader range of coverage of resistant cells in a heterogeneous tumour population
Prevents or slows the development of drug resistant cells
Select cytotoxic drugs:
-with different mechanisms of action
-with different dose limiting toxicities to minimise damage to any one organ system
-in optimum dose and schedule
-with minimum interval between cycles
-monitoring response, performance status and toxicity
Toxicity
Low therapeutic index
Toxicity to normal cells is major limiting factor
Careful dose calculation
-body surface area or derived from renal function
-individual dose adjustment based on prior dose toxicity
‘Reversible’ chemotherapy toxicities
Affects rapidly dividing cells:
-bone marrow- myelosuppression
-GIT- mucositis, diarrhoea
-hair follicles- alopecia
-germinal epithelium
-skin
NB ‘reversibility’ reflects compartment repopulation by recruitment of resting stem cells and this dictates time for recovery between treatment cycles
