Chemotherapy Drugs Flashcards
Cell Cycle
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)
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
In tumours
Mutations in apoptotic genes
Telomerase expressed – enzyme which stabilizes telomeres
Overexpression of growth factors → unrestrained cell growth
Angiogenesis
Angiogenesis
growth of new blood vessels (requires GFs)
Needed for tumour to grow beyond 1-2mm in diameter.
Growth Factors
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
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
Primary tumour –>
Produces enzymes which break down ECM (e.g. metalloproteinases) –>
Invades nearby tissue –>
Grows new blood vessels (angiogenesis) –>
Cells transported via blood or lymphatic vessels –>
Secondary Tumour
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.
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
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
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
Impaired wound healing
Loss of hair
Damage to GI epithelium (inc. mouth)
Growth stunted (children)
Reproductive system → sterility
Teratogenicity
Bleeding/ bruising – due to lack of platelets/ clotting factors
Hair follicle cells are rapidly dividing cells.
Others: Nausea + vomiting, kidney damage
Teratogenicity
congenital malfunctions
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
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)
DNA strands unpaired in S phase (DNA synth) – susceptible to alkylation; DNA cannot separate into single strands.
AML (Acute Myeloid Leukaemia) – too many immature wbcs which do not mature.
Classes of alkylating agents
Nitrogen mustards
Nitrosoureas
Platinum compounds
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)
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).
Estramustine
Estramustine is an analogue of estrogen and therefore stops cell division and has a hormonal effect
NITROGEN MUSTARD
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
Lomustine (CCNU)
Hodgkin’s disease resistant to conventional therapy, malignant melanoma and certain solid tumours
NITROSOUREAS
Carmustine (BCNU)
multiple myeloma, non-Hodgkin’s lymphomas, and brain tumours (e.g. glioblastomas)
NITROSOUREAS
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
Cisplatin - testicular, lung, cervical, bladder, head and neck, and ovarian cancer
Carboplatin – derivative of cisplatin
Less side-effects – can be given as outpatient. But, more myelotoxic
Carboplatin - advanced ovarian cancer and lung cancer
Oxaliplatin – used to treat colorectal cancer (with fluorouracil and folinic acid)
Cisplatin
testicular, lung, cervical, bladder, head and neck, and ovarian cancer
PLATINUM COMPOUND
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.
Carboplatin -
advanced ovarian cancer and lung cancer
derivative of cisplatin
Less side-effects – can be given as outpatient. But, more myelotoxic
PLATINUM COMPOUND
Oxaliplatin
used to treat colorectal cancer (with fluorouracil and folinic acid)
PLATINUM COMPOUND
MYELOTOXIC
bone marrow suppression
Busulfan
selective for bone marrow → leukaemia treatment
ALKYLATING AGENT
Procarbazine
used to treat Hodgkin’s disease
Can cause hypersensitivity rash + inhibits MAO
ALKYLATING AGENT
Trabectedin
soft tissue sarcoma/ advanced ovarian cancer
hepatotoxic
ALKYLATING AGENT
Antimetabolites
Folate antagonists
Folate essential for DNA synthesis/ cell division
E.G. METHO
methotrexate
methotrexate – inhibits dihydrofolate reductase
Given orally, i.m., i.v. or intrathecally
Low lipid solubility – does not readily cross b.b.b.
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.
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
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.
PYRIMIDINE ANALOGUES
Capecitabine
- colon/ colorectal cancer (2nd line treatment for advanced/ metastatic breast cancer)
PYRIMIDINE ANALOGUES
Cytarabine
- acute myeloblastic leukaemia
PYRIMIDINE ANALOGUES
Gemcitabine
– palliative treatment in elderly patients, advanced pancreatic/ bladder/ ovarian/ breast cancer
PYRIMIDINE ANALOGUES
Purine analogues
Compete with A + G – inhibit purine metabolism
E.g. mercaptopurine/ tioguanine (used mainly in leukaemia treatment), pentostatin, fludarabine
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
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
Doxorubicin
- acute myeloblastic leukaemia
CYTOTOXIC ANTIBIOTIC
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
metastatic germ cell cancer (sometimes non-Hodgkin’s lymphoma)
CYTOTOXIC ANTIBIOTIC
dactinomycin
paediatric cancers
CYTOTOXIC ANTIBIOTIC
mitomycin
given i.v. to treat upper GI + breast cancers, by bladder instillation for superficial bladder tumours
CYTOTOXIC ANTIBIOTIC
Plant derivatives
Vinca alkaloids
Taxanes
Etoposide
Vinca alkaloids
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)
Taxanes
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
Paclitaxel – may get pain along vein if infused too quickly.
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
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 - proliferating cells more susceptible to drugs (easier to destroy)
Diethylstilbestrol sometimes used to treat prostate cancer (not usually 1st line therapy due to side-effects).
HORMONE
gynaecomastia
enlargement of a man’s breasts, usually due to hormone imbalance or hormone therapy.
Progestogens
Megestrol, medroxyprogesterone, norethisterone
Used to treat endometrial cancer
HORMONE
GnRH analogues
Goserelin, buserelin, leuprorelin, triptorelin
inhibit GnRH rel. → ↓ LH/ FSH → ↓ testosterone
Used to treat prostate cancer/ advanced breast cancer (in premenopausal women)
HORMONE
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
Hormone antagonists
Flutamide, cyproterone, bicalutamide
Letrozole/ exemastine
Tamoxifen (+ fulvestrant)
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
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
HORMONE ANTAGONIST
Letrozole/ exemastine
Letrozole/ exemastine (aromatase inhibitors)
Block conversion of androgens to oestrogens
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.
HORMONE ANTAGONIST
Flutamide, cyproterone, bicalutamide
Androgen antagonists → prostate cancer treatment
HORMONE ANTAGONIST
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
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)
. 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)
MONOCLONAL ANTIBODY
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
MONOCLONAL ANTIBODY
Ofatumumab
Used to treat resistant chronic lymphocytic leukaemia
MONOCLONAL ANTIBODY
Bevacizumab
Treatment of colorectal cancer Neutralises VEGF → prevents angiogenesis Given i.v. (usually with other drugs) VEGF overexpressed in many tumours MONOCLONAL ANTIBODY
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.
Treatment regimes
Cytotoxic drugs often given in combination –
↑ 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) –
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
Mephalan
- multiple myeloma, childhood neuroblastoma, localised soft-tissue sarcoma of the extremities
NITROGEN MUSTARD
Chlorambucil/ bendamustine –
lymphomas, chronic leukaemias
NITROGEN MUSTARD
Bendsmustine
lymphomas, chronic leukaemias
NITROGEN MUSTARDS
