5 Chemotherapy Drugs Flashcards
Objectives
Define cancer What causes it? Different treatments What are the general side effects? Drugs – mechanisms + side-effects Treatment regimes Control of side-effects
Cancer statistics
In 2011, 331,487 people were diagnosed with cancer in the UK
200 types of cancer with different causes, symptoms and treatments
every 2 minutes someone in the UK is diagnosed
Breast, lung, bowel and prostate cancers together account for over half of all new cancers each year
can develop at any age - most common in older people.
Cancer incidence rates up by > 33% since 1970s!
Less than 1% cancers in under 24s BUT > 60% in over 65s
Worldwide ~12.7 million new cases of cancer (2008)
Annual cost to NHS = £5 bn*
large increases strongly linked to lifestyle choices, such as kidney, liver, malignant melanoma (skin), oral and uterine (womb)
About a third of cancers are caused by smoking, diet, alcohol and obesity!
In last decade the incidence rate of stomach cancer has decreased by more than a quarter for both sexes.
The male lung cancer incidence rate has decreased by almost a sixth.
over half of new cancers (08) were in developing countries.
N.B. Cost to society = £18 bn/ year including loss of productivity!
What is cancer?
normal cell - uncontrolled proliferation - tumour
Loss of function
Invasive
Ability to metastasize
Lack invasive properties
Unable to metastasize
normal cell programmed to divide at certain time intervals and a set number of times before dying
has a predefined function - genetically determined or may be influenced by chemicals it is exposed to.
Benign tumours may be asymptomatic but may compress vital organs or blood vessels, necessitating their removal.
What causes cancer?
normal cell - DNA mutation - cancer cell
Inherited
e.g. defective BRCA1/ 2 genes in breast cancer; deficiency in DNA repair enzymes
Acquired
e.g. viruses, carcinogens (asbestos, smoking, radiation, etc), alcohol, drugs, sun exposure, geographical location
Carcinogenesis is multifactorial (requires several events to occur)
Cell cycle
G1 -Gap1 G0 - (cells no longer dividing S phase - DNA synthesis G2 - Gap 2 M - Mitosis
Each cell undergoes a continuous cell cycle.
Mitosis involves the 2 DNA chains separating - each chain is then copied (transcribed), catalysed by DNA polymerase.
several genes regulate this process to ensure that mutations are rare.
After mitosis, daughter cells enter a growth phase (G1) – some cells will leave the cycle because they have reached the end of their replication lifespan or because they are resting but capable of re-entering the cycle.
After a period of growth there is a period of DNA synthesis, which is followed by another growth phase (G2) which precedes further cell division.
All of these phases are highly regulated by specific genes and pathways.
How is cell growth normally regulated?
Growth factors – have specific Rs/ signalling pathways
Cell cycle transducers
Apoptotic genes – induce programmed cell death in aging/ abnormal cells
Telomeres – cap chromosomes (shorten with age until replication ceases)
VEGF stimulates growth of new blood vessels – has two distinct Rs, linked to different signaling pathways
Cell cycle transducers respond to a signal such as a GF by altering intracellular molecules inside the cell
Apoptosis - vital process to ensure that aging cells do not exceed their useful lifespan
Telomeres - regions of repetitive nucleotide sequences at each end of a chromosome - protect the end of the chromosome from deterioration or from fusion with neighbouring chromosomes
Telomeres allow chromosome ends to shorten during chromosome replication.
Oncogenes
Proto-oncogenes:
normal genes which can mutate to become oncogenes
code for proteins involved in cell division/ proliferation
have the potential to cause cancer (40 different proto-oncogenes known - 14 identified with a high chance of causing cancer!)
i.e. when they become oncogenes, the oncogene produces large amounts of the normal proteins which means that cell survival is promoted, enabling cells which should be killed to survive and proliferate (i.e. Anti-apoptotic)
Normally mutated or expressed at high levels in tumour cells
Usually requires mutations in other genes to cause cancer
Environmental factors or viral infection may trigger oncogenes to cause cancer.
Gene mutations which can lead to cancer
In promoter region → ↑ transcription
Gene amplification → more copies of proto-oncogene
Chromosome translocation → proto-oncogene moved to new site where protein expression more likely
Fusion of proto-oncogene with another gene → protein with more activity
Examples of products of proto-oncogenes include EGF-Rs, VEGF-Rs and HER-2.
In tumours
Mutations in apoptotic genes
Telomerase expressed – enzyme which stabilizes telomeres
Overexpression of growth factors → unrestrained cell growth
Angiogenesis – growth of new blood vessels (requires GFs)*
- Needed for tumour to grow beyond 1-2mm in diameter.
cells which would normally die continue dividing
Telomerase stops telomeres from getting shorter by elongating them after every replication cycle. Scientists were excited by the discovery because it has implications for treating diseases which cause premature aging (e.g. Progeria) BUT increased risk of cancer.
GFs normally expressed by cells for the purposes of natural growth and wound healing. If they are overexpressed then cell growth can get out of control.
Dedifferentiation in tumour cells
Normally stem cells produce daughter cells which, when exposed to specific signals, will differentiate into cells with a specialised role.
*These are fitted with a safety mechanism so that if they end up in the wrong tissue then they lose their survival signals and die.
In tumours, the daughter cells, instead of becoming more specialised, revert back to an earlier developmental stage and are less specialised.
Adult stem cells divide during tissue repair and normal cell turnover (found in bone marrow, adipose tissue and blood).
Metastasis
i.e. location of secondary tumour depends on chemical signals expressed by certain tissues which are recognised by tumour cells (e.g. breast cancer → kidney).
Objectives of cancer therapy
Curing patient (i.e. eliminating all traces of cancer) Prolonging life (shrinking tumours to alleviate symptoms) Palliative therapy (reducing pain, improving QoL)
Cancer treatment
Surgery (removal of solid tumours)
Irradiation (radiotherapy) – Wk 12 lecture
Drug therapy (chemotherapy)
Combination of the above
Difficulties in treating cancer
May be asymptomatic until late stage
Detection methods not 100% reliable
May be hard to find primary site (or metastases)
Cancer cells v. similar to normal cells
Difficult to exploit biochemical differences
i.e. therapy toxic to normal tissue
Symptoms - compression of nerves (pain) or inhibition organ function or detection of a solid mass (lump)
Often symptoms similar to (or the same as) other diseases
May not show up on scans
Abnormal blood test results could be produced by other conditions
Secondary tumour may be discovered first (e.g. Brain, lung, liver, lymph node and bone) so primary site hard to find.
Tumour cells often have the same signalling molecules/ pathways as normal cells
Drugs are so toxic that patients can die from side effects.
Compartments
In a solid tumour, cells occupy 1 of 3 ‘compartments’:
A - Dividing Cells
B - Resting cells (in G0) phase capable of dividing
C - Cells no longer dividing but contribute to tumour volume
N.B. Only cells in compartment A susceptible to most cytotoxic drugs (may be as few as 5%!)
Aims of chemotherapy
To kill ALL malignant cells in the body
i.e. if a drug kills 99.99% of cells in a tumour containing 1011 cells, how many viable cells will remain?
Answer: ………………
N.B. Cannot rely on immune system to kill the rest – why not?
Compare to bacterial infection - immune system capable of fighting off any bacteria which remain
Immune system unable to recognise tumour cells as foreign because essentially normal cells.
Toxic effects of chemotherapy
Drugs affect all rapidly dividing normal tissues: Bone marrow suppression – outcome? Impaired wound healing Loss of hair Damage to GI epithelium (inc. mouth) Growth stunted (children) Reproductive system → sterility Teratogenicity Others?
Possible targets for anti-cancer drugs
Hormonal regulation of tumour growth
Defective cell cycle controls
Classes of anticancer drugs
- Cytotoxic (alkylating, antimetabolites, antibiotics, plant derivatives) – block DNA synthesis/ prevent cell division
- Hormones (+ their antagonists) – suppress opposing hormone secretion or inhibit their actions
- Monoclonal antibodies – target specific cancer cells
- Protein kinase inhibitors – block cell signalling pathways in rapidly dividing cells
1a. Alkylating Agents
Target cells in S phase
Form covalent bonds with DNA (crosslinking) – prevent uncoiling → inhibits replication
Additional side-effects with prolonged use: sterility (esp. men) + ↑ risk of non-lymphocytic leukaemia (AML)
i.e. DNA strands unpaired in S phase (DNA synth) – susceptible to alkylation; DNA cannot separate into single strands.
NLL (Acute Myeloid Leukaemia) – too many immature wbcs which do not mature.
Classes of alkylating agents
Nitrogen mustards
Nitrosoureas
Platinum compounds
Others
Nitrogen Mustards
Mustard gas developed as weapon in WWI
Mechlorethamine – 1st anti-cancer drug (Goodman/ Gilman, 1942)
V. reactive – only given i.v.
E.g. cyclophosphamide, melphalan, chlorambucil, bendamustine, estramustine (prostate cancer)
Discovered whilst investigating toxicity of N mustards during WWII.
Found in animal models to have cytotoxic effects, particularly in tissues with rapid turnover of cells e.g. lymphoid tissue, bone marrow + GI epithelium
Worked on an oestrogen-induced tumour in a mouse (which started to regress soon after injection of the compound).
Melphalan - multiple myeloma, childhood neuroblastoma, localised soft-tissue sarcoma of the extremities
Chlorambucil/ bendamustine – lymphomas, chronic leukaemias
Estramustine is an analogue of estrogen and therefore stops cell division and has a hormonal effect
Bendamustine – lymphomas, chronic leukaemias
Cyclophosphamide
Prodrug – can be administered orally → activated in liver to phosphoramide mustard + acrolein
Acrolein → haemorrhagic cystitis (can be prevented by administering large volumes of fluid)
Set up alongside a saline drip to ensure that it is flushed through with large volumes of fluid.
Nitrosoureas
Highly lipophilic – cross b.b.b. → CNS tumours
Carmustine (BCNU) – given i.v.
Lomustine (CCNU) – given orally
Carmustine - multiple myeloma, non-Hodgkin’s lymphomas, and brain tumours (e.g. glioblastomas)
Lomustine - Hodgkin’s disease resistant to conventional therapy, malignant melanoma and certain solid tumours
