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.
