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Molecular Basis of Cancer Therapy - Coggle Diagram
Molecular Basis of Cancer Therapy
Chemotherapy
Difference between normal and cancer cells
Take advantage of this to target cancer cells
Kill/prevent growth of cancer cells
Normal cells unaffected
Some drugs cannot distinguish between normal + cancer cells
Toxicity of chemotherapeutic agents to normal cells
Unpleasant side effects
Value is in the chemotherapeutic agents having definite selectivity for killing cancer cells over normal cells
Normal tissue repairs + regrows
Chemical agents
Anti-cancer
Cytotoxic
Primarily drugs that interfere with DNA synthesis + mitosis
Systemic treatment
Recommended for cancer that has spread throughout the body + tumours that occur at more than one site
Less mutilating than surgery
Helps to conserve organ/limb function
Chemotherapy strategies
Neoadjuvant
Preoperative treatment/tumour shrinkage
Increases effectiveness of other cancer treatments
Adjuvant
Postoperative/risk of recurrence
Often given after other therapies have destroyed clinically detectable cancer cells
Prolonged survival
Pallitative
No curative intent/improved life expectancy
Minimise discomfort caused by cancer
Combined modality
Use of drugs with other cancer treatments
Combination
Simultaneous treatment with several anti-cancer drugs
Classes of conventional anticancer drugs
DNA reactive drugs
Bifunctional alkylating agents
Two functional alkyl groups
Cyclophosphamide
Most widely-used alkylating agent
Most versatile + useful of the nitrogen mustards
Inactive pro-drug (safe)
Some tumour cells contain high activities of phosphoamidases + phosphatases
Pro-drug selectively activated in tumour cells by P-N cleavage
Most activation is in the liver (mixed function oxidases)
Acrolein by-product
Toxic to bladder
Hemorrhagic cystitis
Co-treated with Mesna (reducing agent)
Also associated with pulmonary, renal, cardiac + hepatic toxicity
Used in breast cancer
Adjuvant therapy
Therapeutic use
Adjuvant
Lymphoma
CLL
Breast cancer
Curative in Burkitts lymphoma
Used in
Non-Hodgkins lymphoma
Ovarian cancer
Oxazaphosphorine
Only cytotoxic after generation of an alkylating species
Followed by hydroxylation by cytochrome p450 enzymes
Intermediate form 4-hydroxy cyclophosphamide further broken down
Active compound phosphoramide
Cytotoxic action is reaction of phosphoramide mustard with DNA
Forms irreversible crosslinks between and within DNA strands at N-7 of guanine
Ifosfamide
Analogue of cyclophosphamide
Prodrug with lower activity
Metabolism similar to cyclophosphamide
Decreased affinity for MFOs slows activity
Increased doses needed for therapeutic effect
Possible increased acrolein
Co-treatment with Mesna more important
Treats
Testicular cancer
Sarcomas
Lung cancer
Toxicities of alkylating agents
Bone marrow
Dose limitin
Mucosal e.g. intestinal ulceration
Neurotoxicity e.g. CNS nausea, ototoxicty
Other organ toxicity e.g. renal
Tending to be superseded by newer treatments now
Improvements
Increase stability of molecule
Allow oral administration
Water solubility
Introduction of ring structures decreases reactivity (weakens Cl leaving groups)
pi electrons in benzene ring interact with lone pair on N, reducing potency
e.g. chlorambucil used to treat chronic lymphocytic leukaemia
Platinum compounds
Cisplatin and carboplatin
Newer treatments
Oxiplatin
Satraplatin
Action similar to N-mustards
Strong Cl leaving groups can be reduced by nucleophiles
Reacts at N-7 and O-6 of guanine
Formation of intrastrand cross-links + adducts
Available for general oncology practice in 1978
Used to treat some solid tumours
Breast
Testicular
Lung
Ovarian
Cisplatin shown to have broad spectrum of anti-tumour activity in variety of animal systems + in clinical practice
Cisplatin
Kill tumour cells as direct consequence of the damage caused by their reaction with DNA
Binds to N-7 of guanine
Forms inter-/intrastrand crosslinks that inhibit RNA/DNA synthesis
Good activity in range of adult + paediatric tumours
Often used in combination with antimetabolite drugs
Repair of DNA damage requires de novo synthesis of nucleotides
Clinical activity
Germ cell tumours
Ovarian cancer
Head + neck cancer
Bladder cancer
Childhood cancers
Severe acute and long-term toxicities
Nephrotoxicity
Neurotoxicity
Ototoxicity
Hearing + balance problems
Nausea + vomiting
Carboplatin
Greatest benefit of carboplatin relative to cisplatin is reduced side effects
Elimination of nephrotoxicity
Lacks most of non-haematological toxicities of cisplatin
Analogue of cisplatin
Cyclobutane dicarboxylic acid - more stable leaving group
Activity equal to cisplatin
Longer T\(_{\frac{1}{2}}\) than cisplatin
Mono-functional alkylating agents
Bind directly to DNA
Disrupt or prevent replication
Strand breaks, crosslinks + abnormal base pairing
Chemically diverse drugs
Functional alkyl group
Highly reactive at nucleophilic sites
Lots of nucleophilic sites in DNA bases
Alkylate bases in DNA
Nitrogen mustard
Contains chloride groups
Similar to mustard gas (war weapon)
Too reactive for use in body
Currently used in MOPP
With oncovin, procarbazine and prednisolone
MOPP is used in lymphomas
Antimitotics
Disrupt structure + organisation of DNA during cell division
By inhibiting the function of microtubules
Cytoskeleton + microtubules
Cytoskeleton important for structural organisation in cell
Consists of microfilaments
Microtubules are a type of microfilament
Formed by \(\alpha\)-tubulin and \(\beta\)-tubulin heterodimers
Tubulin polymerisation + microtubule breakdown are active, dynamic processes
Microtubule formation or breakdown altered
Cell death
Formation of microtubules critical for spindle during mitosis
In metaphase
Crucial role in mitosis makes them prime target for anticancer agents
Also important in critical cell functions
Transmission of signals
Support of intra-cellular systems
Often referred to as spindle poisons
2 major classes
Vinca alkaloids
Examples
Vinblastine
Vindestine
Vinorelbine
Vincristine
Side effects
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Treatment
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Mechanism
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Alkaloids extracted from Madagascar periwinkle
Bind to tubulin
Prevent microtubule formation
Block ability to polymerise with \(\alpha\) subunit
Balance of tubulin assembly and disassembly pushed towards disassembly
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Through \(\beta\) subunit
Used in
Hodgkin's disease + lymphomas
Advanced cancer
Leukaemia
Taxanes
Examples
Docetaxel
Paclitaxel
One of most important developments in treatment of epithelial ovarian cancer
Used in combination with carboplatin
Toxicities
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Pre-medication with anti-histamines and steroid used to prevent hypersensivity
Taxol
Active compound isolated by chemistry + structure determined by crystallography
Microtubule stabilisers
Bind tubulin
Enhance + stabilise spindle assembly
Balance between assembly + disassembly tilted in favour of formation of large, inappropriate microtubular structures
Prevents microtubules being broken down
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Extracted or semi-synthetic from yew trees
Side effects
Myelotoxicity
Neurotoxicity
Anaphylactic reactions
Active in a broad range of solid tumours
Breast
Lung
Advanced prostate
Topoisomerase I/II inhibitors
Intercalating agents
Non-intercalating
Antimetabolites
2 major classes
Nucleoside analogues
Purine analogues
Pyrimidine analogues
Antifolates
Analogues of vitamin folic acid (B\(_9\))
Compete with natural folates in the cell
Folate dependent enzymes are involved in synthesis of
Thymidine nucleotides for DNA
Purine nucleotides for DNA and RNA
Most inhibit dihydrofolate reductase (DHFR) e.g. methotraxate and/or thymidylate synthase (TS)
Methotrexate
Analogue of folic acid
Enters cells by active transport
Can be polyglutamated (prevents efflux)
Competitive inhibitor of dihydrofolate reductase
Prevents renewal of THF pool
No DNA synthesis
Most commonly used antifolate
Similar to natural folates
Same transport mechanisms to enter cell
Folate receptor + reduced folate carrier
Acted on by same modifying enzymes
Polyglutamation (enzymatic addition of multiple glutamic acid residues)
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Toxic to any proliferating cell
Reduced folate (leucoverin) given after 24h to reduce side effects + allow higher acute dose of methotrexate
Administration
Oral
IV
IM
Intrathecal (CSF)
Used in
Breast cancer
ALL
Bronchial
Sarcoma
Problems
Resistance
Kidney damage
Proliferating cells need pool of nucleotides for DNA replication to proceed
Class of drugs developed to interfere with aspects of nucleotide metabolism
Often chemical analogues of normal cellular biochemicals used in nucleic acid synthesis
Typically cause death in S phase of cell cycle
Tubulin binders
Vinca alkaloids
Taxanes
Side effects
Toxic to other proliferating tissues
GI tract
Bone marrow
Hair follicles