Cancer 1 Flashcards
What are the key features of cancer
Cancer is a collection of diseases with the common feature of uncontrolled growth
Several cellular changes (DNA mutations etc) are required to generate cancer.
Cancers can be restricted to the tissue of origin (local disease) or they invade other tissues = METASTASIS
Once a cancer has metastasised it is much more difficult to treat
What are the hallmarks of cancer
Insensitivity to growth inhibitors, self sufficiancy in growth signals, limitless replicative potential, sustained angiogenisis, evasion of apoptosis, tissue invasion and metastasis (all supposrted by an inflammatory microenvironment)
How does a cell aquire cancerous hallmarks
These hallmarks are acquired by the cell via mutations
There are more than ….. types of cancer, each with different causes, symptoms and treatments.
More than 1 in…… people in the UK will develop some form of cancer during their lifetime.
Cancer can develop at any age, but is most common in older people. More than …. in …. cancers are diagnosed in people aged 65 and over
There are more than 200 types of cancer, each with different causes, symptoms and treatments.
More than 1 in 3 people in the UK will develop some form of cancer during their lifetime.
Cancer can develop at any age, but is most common in older people. More than three out of five cancers are diagnosed in people aged 65 and over
Almost ….. people a day are diagnosed with cancer, one person every 2 minutes
Over …% of cancers are preventable
Almost 1000 people a day are diagnosed with cancer, one person every 2 minutes
Over 40% of cancers are preventable
Cancer incidence rates have risen by … in males and by … in females since the mid-1970s.
There have been large increases in the incidence of many cancers strongly linked to ….
…. of people diagnosed with cancer (in the UK) now survive their disease for at least five years.
Cancer survival rates in the UK have doubled in the last …. years.
Cancer incidence rates have risen by 20% in males and by 40% in females since the mid-1970s.
There have been large increases in the incidence of many cancers strongly linked to lifestyle choices (smoking, alcohol and BMI)
Half of people diagnosed with cancer (in the UK) now survive their disease for at least five years.
Cancer survival rates in the UK have doubled in the last 40 years.
What are the 4 types of cancer treatment
Surgery
Radiotherapy
Targeted therapy
Chemotherapy
What is the main problem with chemotherapy
Chemotherapy prevents cell growth
Some normal tissues also have rapid cell growth which will lead to hair loss, sickness, diarrhoea and a weakened immune system
What kind of theraputic index does chmotherapy drug have
very small! this is why it has such severe side effects
Where are the most rapidly dividing cells found
Hair follicles, gi tract, bone marrow (Chemotherapy affects the rapidly dividing cells of the bone marrow
Makes patients more susceptible to infection
Regular blood tests for monitoring)
How can we manage the side effects of chemotherapy drugs if they become too much for the patient to handle
Reduce dose
Increase window between doses
Additional drugs to mitigate side effects
Cessation of treatment
What are the two modes of action for chemotherapy
Both center around targetting DNA
- Direct interaction with DNA
- Prevention of nucleic acid synthesis by inhibiting one or more of the enzymes involved in DNA/RNA synthesis
What are the 3 types of drugs which directly target dna
Alkylating agents
Metal complexes that bind to DNA
Intercalating agents
What has mustard got to do with cancer treatment
Nitrogen mustard – first drug used in cancer therapy, related to the war gas sulphur mustard and found to have antitumour activity
Sulphur mustard too toxic and reactive but isosteric nitrogen mustard less toxic but still very reactive with toxic side-effects
Still in clinical use in combination with other drugs
Which part of the DNA do the alkylating agents (mustards) target
Alkylating agents attach and alkyl group to DNA (guanine)
This causes linkages between strands of DNA that inhibits DNA synthesis - hence its cytotoxic
Alkylating agents will also target normal cells that divide frequently (GI tract, bone marrow, testicles and ovaries – infertility)
Alkylating agents are carcinogenic in their own right – long term side effects
How do we reduce the toxicity of the alkylating agents
- Only form the electrophile slowly in the tumour:
Example - CHLORAMBUCIL
Nitrogen lone pair delocalised onto aromatic ring, making electrophile formation more difficult.
One of the least toxic nitrogen mustards
- Attach alkylating agent to an “amino acid”:
Example - MELPHALAN
Tumours require a large quantity of amino acids for protein synthesis
Drug enters tumour cell by the phenylalanine amino acid transporter
- Pro-drug – requiring reductive activation. Tumours have a highly reductive enviroment. These drugs only work in these environments hence can differentiate between cancer and regular cells.
Example -
MITOMYCIN C
Which cancers do we use dna alkylating agents in
- Hodgkins disease, Non-Hodgkins lymphoma, Chronic lymphocytic leukaemia, lung cancer.
- Multiple myeloma, advanced ovarian adenocarcinoma, advanced breast cancer, childhood neuroblastoma
- Upper GI cancers, breast cancer and bladder cancer
Which drugs do we use for
CML
Glioblastoma
Glioblastoma, melanoma
Busulfan - CML
Dacarbazine - Glioblastoma
Temozolomide -Glioblastoma, melanoma
Summarise the mechanism of alkylating agents
Contain highly electrophilic groups
The groups form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine)
Prevent replication and transcription by crosslinking the two DNA strands preventing it from opening - cytotoxicity
Toxic side effects (highly proliferating normal tissues)
2nd generation drugs have been developed to reduce toxicity of the alkylating agents usually to reduce the electrophilicity (e.g. melphalan, chlorambucil and Mytomycin C)
Alkylation of nucleic acid bases can result in miscoding (mutation) - potentially carcinogenic
How do metal complexes that bind to dna target cancer cells
Neutral inactive molecule acting as a pro-drug
Platinum covalently linked to chloro substituents prevent it from linking to DNA
Ammonia molecules act as ligands and remove the chloride ions and replace them with water (only occurs in low chloride ion enviroments)
Activated in cells with low chloride ion concentration (cancer cells have lower levels than normal tissue)
Chloro-substituents replaced with neutral water ligands
This produces positively charged species
e.g. cisplatin (platinum)
How does cisplatin work and what are its side effects
Binds to DNA in regions rich in guanine units
Intra-strand links (rather than inter-strand)
Toxic side-effects limited initial clinical application;
(i) severe nausea and vomiting (ii) nephrotoxicity (kidneys) (dose limiting) (iii) ototoxicity (ears) (iv) bone marrow suppression
How do we minimise the side effects of cisplatin
Side effects have been overcome with improved administration and hydration procedures and co-administration of anti-sickness medication e.g.metoclopramide
How do intercalating agents interact with cancerous dna
It slides in between the stacked dna bases bases
It is a planar tetracyclic chromophore which is inserted between adjacent dna pairs
Its position is stabilised by electrostatic interactions between DNA phosphate groups and the +vely charged amino group of the sugar moiety
As a result in inhibits the action of topoisomerase II
Generates oxygen free radicals which causes DNA damage
Give an example of an intercalating agent
Doxorubicin
What are the side effects of Doxorubicin (adriamycin)
Nausea and vomiting
Myelosuppression
Alopecia
Cardiotoxicty (develops up to 6 months after the last dose)
The cardiotoxicity is reduced by DEXRAZOXANE which has an EDTA-like structure and removes Fe from adriamycin
What is doxorubicin used to treat
Used to treat breast cancer, bladder cancer, sarcoma and lymphoma
How do DNA topoisomerases work
Topoisomerases modify the topological state of DNA by inducing either transient single strand (topo I) or double strand (Topo II) DNA breaks (think of headphones)
This process is essential for uncoiling DNA for subsequent replication, transcriptional, repair or recombination processes
How do topoisomerase inhibitors work
Topoisomerase inhibitors block the action of topoisomerase (after it has broken the dna) and as a consequence elicit a permanent single stranded (topo I) or double strand (topo II) DNA strand breaks
How does topoisomerase II work
Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand
Tyrosine residues in the enzyme are involved in the chain breaking process
The residues form covalent bonds to DNA
The enzyme pulls the chains apart to create a gap
The intact strand of DNA is passed through the gap
The break is resealed
Give an example of a topoisomerase inhibitor
ETOPOSIDE
A semisynthetic derivative of PODOPHYLLOTOXIN poison extracted from the Mandrake plant.
Forms a ternary complex with DNA and the topisomerase II enzyme
Prevents DNA re-ligation (joining back together) = double strand breaks
Causes errors in DNA synthesis = cytotoxic
What are the clinical uses of etoposide
Has been used for more than a decade
Effective only in chemo-sensitive tumours such as leukaemias, testicular cancer and small cell lung cancer.
What are the advantages and the side effects of etoposide
Major advantage - doesnt have any long term irreversible organ specific toxicity (compared to cisplatin or doxorubicin).
Myelosuppression
Nausea and vomitting
Hair loss
How do the anti-metabolites work
Anti-metabolites interfere with the production of nucleic acids
- Inhibit the production of deoxyribonucleoside triphosphates (DNTPs), the precursors of DNA synthesis.
- Inhibits the formation of normal precursors of nucleic acid by competing for metabolic enzymes - Some are similar in structure to normal purine or pyrimidine bases and the drugs are substitute for them in anabolic pathways.
- The drugs get incorporated into RNA and DNA instead of normal triphosphates
What are some examples of anti-metabolites
5-FU, Capeciabine (thymidylate sythase inhibitor)
Methotrexate (inhibits dihydrofolate reductase (DHFR)) enzymatic inhibitor
Gemcitabine (cytidine analogue) enzymatic inhibitor
Descibe the cell cycle
The cell cycle is a four-stage process in which the cell increases in size (gap 1, or G1, stage), copies its DNA (synthesis, or S, stage), prepares to divide (gap 2, or G2, stage), and divides (mitosis, or M, stage). The stages G1, S, and G2 make up interphase, which accounts for the span between cell divisions.
What is Vincristine and how does it work
Its used in leukemia & Hodgkin’s disease and
prevents polymerization of microtubules hence preventing mitosis
Isolated from periwinkle
What is Taxol and how does it work
Used in lung, ovarian, breast cancer, Kaposi’s sarcoma and it binds to and stabilizes microtubules in the M phase preventing the movement through to G1.
Isolated from pacific yew treee
