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
Platinum compounds
E.g. cisplatin
Potent alkylator
Binds to RNA > DNA > protein
Binds to purine bases (i.e. G, A, U)
resistance may develop → DNA repair by DNA polymerase
Testicular/ ovarian cancer – low levels of repair enzymes (i.e. more sensitive to drug)
Given by slow i.v. injection/ infusion*
Discovered by accident by scientists studying effects of electrical fields on bacterial growth – Pt leached off electrodes + formed a reactive chemical.
*May take up to 8 hours!
Cisplatin - testicular, lung, cervical, bladder, head and neck, and ovarian cancer
Side effects - Cisplatin
V. nephrotoxic – requires hydration/ infusion
Causes severe nausea/ vomiting
Risk of tinnitus, peripheral neuropathy, hyperuricaemia (gout) + anaphylaxis
Patients may be given extra fluid to drink and asked to record how much they drink/ urinate.
P.N. - Numbness, tingling in hands/ feet.
Changes in taste.
Other Pt compounds
Carboplatin – derivative of cisplatin
Less side-effects – can be given as outpatient
But, more myelotoxic
Oxaliplatin – used to treat colorectal cancer (with fluorouracil and folinic acid)
Myelotoxic – bone marrow suppression
Carboplatin - advanced ovarian cancer and lung cancer
Other alkylating agents
Busulfan – selective for bone marrow → leukaemia treatment
Procarbazine – used to treat Hodgkin’s disease
Can cause hypersensitivity rash + inhibits MAO
Trabectedin – soft tissue sarcoma/ advanced ovarian cancer
hepatotoxic
Soft tissue – skin, adipose tissue, muscle.
1b. Antimetabolites
Folate antagonists
Folate essential for DNA synthesis/ cell division
E.g. methotrexate – inhibits dihydrofolate reductase
Given orally, i.m., i.v. or intrathecally
Low lipid solubility – does not readily cross b.b.b.
Mx one of the 1st chemotherapy drugs (1950s)
Intrathecally = injected between bones of lower back into CSF (i.e. lumbar puncture)
Used to treat childhood acute lymphoblastic leukaemia, choriocarcinoma, non-Hodgkin’s lymphoma, and a number of solid tumours.
Methotrexate (contd)
Mostly excreted unchanged in urine – consequences for patients with renal impairment?
NSAIDs can reduce excretion → ↑ toxicity
Tumour cells may develop resistance
In high doses, given with folinic acid (folate derivative) to ‘rescue’ normal cells
Also used to suppress immune system – e.g. in rheumatoid arthritis treatment
i.e. lower doses req’d in patients with renal impairment
Pyrimidine analogues
Compete with C and T bases which make up RNA + DNA → inhibits DNA synthesis
E.g. fluorouracil, capecitabine, cytarabine, gemcitabine
Less well absorbed (orally) than methotrexate – given parenterally
Fluorouracil - solid tumours, including GI cancers and breast cancer, commonly used with folinic acid in advanced colorectal cancer, may also be used topically for certain malignant and pre-malignant skin lesions.
Capecitabine - colon/ colorectal cancer (2nd line treatment for advanced/ metastatic breast cancer)
Cytarabine - acute myeloblastic leukaemia
Gemcitabine – palliative treatment in elderly patients, advanced pancreatic/ bladder/ ovarian/ breast cancer
Purine analogues
Compete with A + G – inhibit purine metabolism
E.g. mercaptopurine/ tioguanine (used mainly in leukaemia treatment), pentostatin, fludarabine
1c. Cytotoxic antibiotics
E.g. doxorubicin – binds to DNA + inhibits DNA/ RNA synthesis
Inhibits topoisomerase II
Given by i.v. infusion
Must be careful to avoid extravasation at injection site* → local necrosis
Can cause cardiac dysrhythmias/ heart failure in high doses†
- precautions?
† Limited to 450 mg/ m2
Red pigment produced by Streptomyces bacteria (hence ‘ruby’cin)
Top II ‘swivels’ DNA and introduces double strand breaks to prevent tangling during replication – involved in unwinding DNA for replication.
Gloves/ eye protection should be worn by nurses
Doxorubicin - acute myeloblastic leukaemia
Other cytotoxic antibiotics
Bleomycin
degrades pre-formed DNA
Active against non-dividing cells (G0)
Causes little myelosuppression BUT causes pulmonary fibrosis in 10% patients
50% patients develop mucocutaneous reactions (mouth sores, hair loss, fungal infections, etc) + hyperpyrexia
Others: dactinomycin (paediatric cancers) / mitomycin
i.e. unlike most cytotoxic drugs, which are active against dividing cells.
Bleomycin - metastatic germ cell cancer (sometimes non-Hodgkin’s lymphoma)
Dactinomycin – paediatric cancers
Mitomycin - given i.v. to treat upper GI + breast cancers, by bladder instillation for superficial bladder tumours
1d. Plant derivatives
Vinca alkaloids
e.g. vincristine, vinblastine, vindesine
Derived from Madagascar periwinkle
Prevent polymerisation of tubulin → microtubules → prevents spindle formation
Effects only occur during mitosis (M phase)
Relatively non-toxic (except vincristine → neuromuscular effects)
VC - Tingling, abdominal cramps, jaw pain.
All used to treat leukaemias, lymphomas, and some solid tumours (e.g. breast and lung cancer)
More plant derivatives
Taxanes E.g. paclitaxel, docetaxel Derived from bark of Yew tree Similar mechanism to vinca alkaloids Used to treat advanced breast cancer paclitaxel/ carboplatin – used to treat ovarian cancer
Etoposide
Derived from mandrake root
Used to treat testicular cancer/ lymphomas
Must avoid skin contact
Can cause rapid fall in blood p. during i.v. infusion
Paclitaxel – may get pain along vein if infused too quickly.
Mandrake – long history of medicinal use. Superstitions about digging up roots (anyone doing so may be condemned to Hell!)
Etoposide - small cell carcinoma of the bronchus, the lymphomas, and testicular cancer
- Hormones
Used in treatment of cancers in hormone-sensitive tissues (e.g. breast, prostate, ovaries)
Tumour growth inhibited by R antagonists, hormones with opposing actions, or drugs which block synthesis of endogenous hormones
Rarely cure disease but reduce symptoms
Oestrogens
Ethinyloestradiol + (Diethylstilbestrol)
Antagonists of androgen-dependent prostate cancer (used in palliative treatment)
Side-effects: nausea, fluid retention, thrombosis; impotence + gynaecomastia ( )
Also stimulate resting mammary cancer cells to proliferate – why is this useful?
Diethylstilbestrol sometimes used to treat prostate cancer (not usually 1st line therapy due to side-effects).
i.e. proliferating cells more susceptible to drugs (easier to destroy)
Other hormones
Progestogens (Megestrol, medroxyprogesterone, norethisterone)
Used to treat endometrial cancer
GnRH analogues (Goserelin, buserelin, leuprorelin, triptorelin)
inhibit GnRH rel. → ↓ LH/ FSH → ↓ testosterone
Used to treat prostate cancer/ advanced breast cancer (in premenopausal women)
Somatostatin analogues (octreotide/ lanreotide) Inhibit cell proliferation/ hormone (CCK/ gastrin) secretion → used to treat hormone-secreting tumours of GI tract
Somatostatin secreted by hypothalamus and also stomach/ intestines –inhibits release of GH/ TSH and gut hormones such as gastrin + CCK → red gut motility + gastric emptying + also pancreatic secretions
Works because tumours reliant on hormone secretion in order to grow.
Lanreotide – also treatment of thyroid tumours
Hormone antagonists
Tamoxifen (+ fulvestrant)
Competitive antagonist at oestrogen Rs → inhibits transcription of oestrogen-responsive genes → breast cancer treatment
Adverse effects: similar to menopausal effects, may cause endometrial cancer + ↑ risk of blood clots
Letrozole/ exemastine (aromatase inhibitors)
Block conversion of androgens to oestrogens
Flutamide, cyproterone, bicalutamide
Androgen antagonists → prostate cancer treatment
either block hormone Rs or block synthesis
Tamoxifen – used to treat oestrogen R-positive breast cancer
In U.S. Tamoxifen approved for prevention of cancer in women at high risk of breast cancer. What sort of hormone is oestrogen?
Aromatase – enzyme involved in key step of oestrogen synthesis.
Aromatase inhibitors act predominantly by blocking the conversion of androgens to oestrogens in peripheral tissues; do not inhibit ovarian oestrogen synthesis - should not be used in premenopausal women.
Glucocorticoids
Prednisolone/ dexamethasone
Inhibit lymphocyte proliferation → treatment of lymphomas/ leukaemias
Counter some side-effects of other anti-cancer drugs (e.g. nausea/ vomiting)
i.e. used as supportive therapy/ in palliative care
What else are these drugs used for?
- Monoclonal antibodies
Produced by cultured hybridoma cells
React with specific target proteins expressed on cancer cells → activates immune system → lysis of cancer cells
Some mAbs activate GF-Rs on cancer cells → inhibit survival/ promote apoptosis
Advantages: targeted therapy → fewer side-effects
Disadvantage: expensive; must be given in combination with other drugs
i.e. hybridoma cells formed by fusing antibody-producing B lymphocytes with B cell cancer (myeloma)
Rituximab
Binds to CD20 protein, expressed on certain lymphoma cells → lysis of B-lymphocytes
Effective in 40-50% cases (when combined with trad. chemotherapy)
Can cause hypotension, chills + fever
Longer term – hypersensitivity (can be fatal)
i.e. used to treat non-Hodgkin’s lymphoma - only useful if the tumour cells express the protein (i.e. Requires biopsy and then staining for CD20)
Other mAbs
Trastuzumab (Herceptin)
Binds to HER2 (a GF-R)
Induces immune resp. + cell cycle inhibitors
HER2 overexpressed in ~ 25% breast cancer patients → rapid prolif. (i.e. aggressive form)
Given with standard drugs → ↑ survival rate*
Can cause tremor, flu-like symptoms, itchy eyes, BP changes, palpitations
- e.g. Slamon et al, 2001 – in 469 patients, 78% survival at 1 yr vs 67% without Herceptin
*randomized clinical trial by Slamon et al, 2001 tested trastuzumab in combination with chemotherapy in 469 patients with previously untreated, HER2-positive, metastatic breast cancer. Patients received first-line chemotherapy either alone or in combination with the antibody. At the time of disease progression, patients receiving chemotherapy alone were permitted to cross over to receive trastuzumab, and those already receiving trastuzumab could continue to receive it at the discretion of their physicians. Thus, all patients had the opportunity to receive trastuzumab.
Patients receiving trastuzumab had a lower death rate at 1 year (22% vs. 33%, P=0.008), a longer median survival (25.1 vs. 20.3 months, P=0.046), and a 20% reduction in the risk of death. i.e. this study showed a significant increase in the median time to progression of disease+improved overall survival, even though the experimental intervention ultimately was available to all the patients. A subsequent randomized trial had similar results (Marty et al, 2005).
Ofatumumab
Used to treat resistant chronic lymphocytic leukaemia
Bevacizumab
Treatment of colorectal cancer
Neutralises VEGF → prevents angiogenesis
Given i.v. (usually with other drugs)
i.e. VEGF overexpressed in many tumours
- Protein kinase inhibitors
Imatinib
Blocks tyrosine kinases involved in GF signaling pathways
Used to treat chronic myeloid leukaemia (CML) – previously poor prognosis
Given orally
Problems with drug resistance
Also: Dasatinib, nilotinib
CML – 90% sufferers have a chromosome defect (the Philadelphia chromosome) which encodes an active tyrosine kinase protein, which leads to uncontrolled cell proliferation.
Resistance may be primary (poor initial response) or acquired (following a period of successful treatment). If resistance develops, options are high dose imatinib or dasatinib or nilotinib.
After introduction of imatinib into routine clinical practice, 5-year relative survival increased from 27.1% in 1990–92 to 48.7% in 2002–04 for all age groups combined.
Treatment regimes
Cytotoxic drugs often given in combination – why?
↑ cytotoxicity without ↑ general toxicity (i.e. drugs have diff. side-effects)
↓ chance of developing resistance to individual drugs
Often given in large doses every 2-3 weeks (usually over 6 months) – why?
allows bone marrow to regenerate ↓ chance of developing resistance to individual drugs
more effective than several small doses
Control of side-effects
Nausea + vomiting (emesis)
↓ patient compliance
Ondansetron/ granisetron – 5HT3R antagonists → effective vs cytotoxic drug-induced vomiting
Metoclopramide – dopamine (D2R) antagonist
Anxiety
Lorazepam - anti-anxiety drug (Benzodiazepine)
Myelosuppression
Stem cell transplant
Autologous: stem cells harvested* from patient + infused back after chemotherapy
Allogenic: stem cells from a matched donor
i.e. collected from blood (by dialysis) or bone marrow
- Lenograstim (recombinant GM-CSF) – used to boost stem cell production → speed recovery of immune system
GM-CSF = granulocyte-macrophage colony stimulating factor
Requires daily subcutaneous injections of growth factor to increase numbers of stem cells in bone marrow – released into blood for harvesting
Infused back into patient after high dose therapy
Autologous still risky because takes time for stem cells to differentiate – risk of hypersensitivity reaction to preservative
Allogenic – donor must be carefully matched to avoid rejection.
Why are some treatments not available on the NHS?
E.g. Kadcyla (Trastuzumab emtansine) – breast cancer drug
mAb (Herceptin) linked to cytotoxic drug (mertansine).
Can extend life by approx 6 months, fewer side effects than other chemotherapy (e.g. sickness, hair loss), offers quality of life (allowing patients to work)
But, not a cure, only effective in 1 in 5 patients (expressing HER-2 gene), very expensive (£90,000/ year/ patient) – NICE will sanction max £30,000/ patient/ year
Who is to blame?
NICE? Need to budget for the whole NHS – if this drug is funded then other patients will miss out
Pharmaceutical industry? Must recoup costs of drug development – this drug took 15 years to develop
Solution?
NICE backs down + offers pharmaceutical company asking price
Pharmaceutical company reduces cost to NHS → receives less income/ patient but potentially more patients so greater return? Or, less return so less money to plough back into drug development?
Patients find other ways of paying for drug treatment (e.g. going abroad, Cancer Drugs Fund – run through NHS England)
Kadcyla – routinely available in several European countries
Roche recorded profits of £7.4 billion last year!
