Anti-cancer chemotherapy Flashcards
What are the types of chemotherapy?
Curative - eliminate all cancer cells.
Adjuvant - after surgery to lower risk of cancer coming back.
Neo-adjuvant - before surgery to shrink tumour for easier removal.
Maintenance - prevent reoccurrence after remission.
Palliative - prolonging life and reducing symptoms.
Why is the therapeutic window important in cancer chemotherapy?
The drugs are not very selective, and are cytotoxic, so there needs to be a good therapeutic window between the host cells and cancer cells.
When the drugs enter the blood stream, they need to remain long enough to have an effect.
Therefore they are normally administered by IV infusion.
What is selective toxicity in chemotherapy?
Cancer cell selective toxicity is difficult to achieve as the host cells and cancer cells have subtle difference.
The active form of a drug at the site of cancer must be at appropriate concentration and for an adequate time.
Cytotoxic drugs affect both normal and cancer cells.
What is therapeutic window of cancer chemotherapy?
The range must be between the dose response (therapeutic) and lethal dose (toxic).
The window is very small, so there are lots of side effects.
What do most cancer cells exhibit that can be targeted in chemotherapy?
Abnormal growth, by self-sufficient growth signalling and insensitivity to anti-growth signals.
DNA instability.
Replication immortalisation.
Invasion and metastasis (leave organs).
Evasion of apoptosis.
Sustained angiogenesis (growth of blood vessels from tumour).
What are cell cycle specific drugs?
5-flurouracil
Act on a specific phase of the cell cycle.
What are cell cycle non-specific drugs?
Cyclophosphamide
Can act on almost all stages of cell cycle mainly on proliferation.
Not in G0 (resting)
What is the relationship of dose response and cell survival in cell cycle non-specific drugs?
Linear relationship.
See picture.
What is the relationship of dose response and cell survival in cell cycle specific drugs?
Downward curve
Have a dose cell survival relationship decreasing exponential.
See picture
What are the general classes of chemotherapy in cancer?
Alkylating agents
Antimetabolites
DNA-binding agents (anthracyclines)
Topoisomerase inhibitors.
Microtubule inhibitors
Molecular targeted agents
Selective oestrogen inhibitors
Biological response modifiers
What are alkylating agents?
Transfer methyl or ethyl groups to DNA - usually guanine.
Transformation of intrastrand cross-links causing:
DNA damage
DNA transcription and translation stopped
Apoptosis
DNA repair, leading to DNA fragmentation.
DNA instability
What are examples of alkylating agents?
Nitrogen mustard - cyclophosphamide, melphalan, chorambucil.
Nitrosoureas - Lomustines, Carmustines.
Alkyl sulphonate - Busulfan.
What is cyclophosphamide?
Inactive pro-drug, converted by oxidase enzymes in the liver to form active metabolites:
4-hydroxycyclophosphamide, aldophosphamide, then oxidised by ALDH to carboxycyclophosphamide then phosphamide mustard.
How does cyclophosphamide work?
It forms covalent links with DNA, leading to cross-linking between DNA strands.
This interferes with DNA replication and transcription, ultimately preventing cancer cells dividing and growing.
Effective when cells divide rapidly.
Nonspecific cell cycle.
Used short term in combination as toxic.
What are platinum compounds?
Don’t have an alkyl group, but act similarly to alkylating agents.
Form DNA-inter/intra- strand DNA protein crosslinks by their charge.
Cisplatin, carboplatin, oxaliplatin.
What is about cancer that antimetabolites work by?
Cancer cells have high synthesis and replication resource requirement.
Use natural sources of purines and pyrimidines from diet or metabolism.
Cancer cells have de novo synthesis - make things from scratch by breaking things down.
Druggable target - can accumulate toxic effect to cancer cells.
What is the de novo synthesis by cancer cells?
Can act on thymidine using the limiting enzymes thymidylate synthase and dihydrofolate reductase to make dTMP and DHF.
These are then used for their growth and synthesis.
What are antimetabolites?
Target the limiting enzymes, where there is no alternative pathway so metabolites aren’t made.
The drugs resemble the substrates, then destruct synthesis and regulation of DNA and RNA as they can’t be made.
This then causes abnormalities in DNA so inhibits further synthesis.
What is the reaction of cancer cells to make pyrmidines?
dUMP is converted to dTMP using thymidylate synthase, which is then used to make cytosine and thymine.
What is the reaction of cancer cells to make purines?
THF and DHF are recycled using thymidylate synthase and dihydrofolate reductase to make guanine and adenine.
What is the selectivity of antimetabolites?
Structural similar or compete with endogenous nucleic acid precursors and act on S-phase.
Partial cancer selectivity.
What is methotrexate?
Targets folate metabolism.
Inhibits thymidine and purine biosynthesis.
Slow reversible competitive inhibitor of dihydrofolate reductase.
Leads to cell death.
What is 5-fluoroucil?
Pro-drug that is activated by phosphorylation to form active 5-fluorodeoxyuridylate.
5-fluorodeoxyuridylate inhibits by binding to thymidylate synthase.
This interferes with thymidylate synthesis, so affects DNA replication.
It is a pyrimidine biosynthesis antimetabolite.
What are anthracyclines?
Antibiotics that bind directly to DNA.
Cause intercalation - DNA strands breech
Inhibit repair of DNA, damages cell using machinery
Create Stable complexes with DNA and topo II enzymes.
Topo II is involved in repair and replication, so the complex leads to fragmentation and apoptosis.
How else do anthracyclines work?
Interstrand crosslinks generates free radicals. The quinone group react with iron to form ROS, causes DNA damage and programmed cell death.
What is Epirubicin?
Intercalates adjacent base pairs in DNA.
Inhibits DNA repair, leading to fragmentation of DNA.
DNA cleavage by topoisomerase II leads to cell death.
What are topoisomerases?
Ubiquitous and essential to prevent and resolve DNA and RNA supercoiling during transcription and replication.
Act at replication forks.
What are the types of topoisomerases?
Topoisomerase I causes single cut in the single strand and then relegate the strand. Inhibited by irinotecan and topotecan.
Topoisomerase II cuts both strands and then relegate. Inhibited by etoposide.
What is etoposide?
Acts on S and G2 phase.
Stabilises the DNA topo II.
Used in sarcoma, lung, testicular cancer.
What are microtubule inhibitors?
Chromatid separation during mitosis is performed by microtubules.
Inhibitors are Cell cycle specific, mainly in M phase.
Types of inhibitor are vinca alkaloids and taxanes.
What are vinca alkaloids?
Anti-mitotic and anti-microtubule.
Interact with B-tubulins, to prevent the assembly of microtubules.
Vincristine is used in breast cancer, lymphomas, leukaemia.
Vinblastine is used in testicular and Hodgkins.
What are taxanes?
Prevent microtubule disassembly.
Bind to B-subunit of tubulin and antagonises depolymerisation of microtubules.
Halts mitosis.
Cells have blocked G2/M phase and driven to apoptosis.
e.g. paclitaxel and docetaxel.
How does cell division begin?
Extracellular signalling such as growth factor to initiate cell division and growth.
Receptor tyrosine kinase bind to ATP and transfers phosphates to tyrosine residues - leading to docking sites downstream signalling proteins.
What are small molecule inhibitors?
They compete for the ATP binding site kinases.
BCR-ABL: imatinib
HER-2: lapatinib
VEGFR: sunitinib
EGFR: erlotinib
What are tyrosine kinase inhibitors?
Tyrosine kinase is often mutated in cancers.
Can be inhibited by imatinib mesylate, which binds ATP binding site and stabilises the inactive form of the kinase.
Used in Philadelphia CML and GIT tumours.
What are monoclonal antibodies?
Either target the extracellular end of the GFR or target chemotherapy to target cells.
Normally used in combination with paclitaxel.
There is individualised treatment based on the expression profile of the tumour.
They are very good at targeting specific proteins.
What are examples of monoclonal antibodies?
HER-2 receptor which is overexpressed in breast cancer, is treated with trastuzumab which interacts with the receptor to affect its function.
Cetuximab targets EGFR, overexpressed in colon cancer.
Non-Hodgkin’s lymphoma and CLL B cells overexpress CD20, targeted by rituximab.
What are selective oestrogen receptor modulators?
SERM are distinct from oestrogen, but interact with the receptors.
Modulators include Tamoxifen, anastrozole, down regulators.
What is tamoxifen?
SERM that competes with oestrogen for the receptor site.
Used in oestrogen receptor positive breast cancer, and prophylaxis in HR patients.
What is anastrozole?
Aromatase inhibitor, competitive inhibitor of aromatase enzyme, blocks the synthesis of oestrogen by binding to the oestrogen receptor.
What are down regulators?
Selective oestrogen receptor down regulators, the antagonist interferes with the binding of oestradiol to oestrogen receptors, induces rapidly down regulation of ER.
Block endocrine dependent independent ER signalling in ER breast cancer.
What are biological response modifiers?
Influence biological response that uses substances made from living organisms to treat disease.
Either naturally in body or made in lab.
Can act indirectly or directly on the tumour.
Programmed cell death protein e.g. pembrolizumab and nivolumab.
How do immunomodulators act indirectly?
Facilitate anti-tumour body response by:
Stimulating or suppress the immune system.
Interleukins 2 recombinant induces cytolytic T cells against the tumour.
What are the complications of cancer chemotherapy?
Inter patient variation.
Induced nausea and vomiting, 5-HT3 receptor antagonists can reduce.
Leakage with tissue necrosis.
Bone marrow suppression.
Infection
Alopecia
Infertility
Teratogenesis (deformities)
Secondary malignancy
What are predictive biomarkers for giving oncology drugs?
DPYD
TPMT
UGT1A1
G6PD
CYP2D6
F5
F2
What is primary chemotherapy resistance?
Persistent disease or recurrence.
Intrinsic resistance to cancer cells before treatment.
Tumour heterogeneity
Tumour microenvironment
Cancer stem cells
microRNA in cancer drug resistance
What are the implications of chemotherapy resistance?
Primary resistance can limit the effectiveness of initial chemotherapy regimens.
The choice of alternative treatments may be considered from the outset.
What is therapy induced resistance?
Initially responsive cancer cells evolve mechanisms to survive and proliferate.
Multidrug resistance
Inhibition of cell death
Changing the drug metabolism
Genetic mutations, that change the drug targets, enhance DNA repair.
What are the implications of therapy induced resistance?
Limited long-term effectiveness of chemotherapy.
Need for change in treatment regimens, including switching drugs or incorporating additional agents to overcome resistance.
