Case 14- Anticancer drugs Flashcards
Adjuvant chemotherapy
After theoretical surgical cure to increase the chance of cure, reduces the risk of relapse, killing any microscopic disease left behind.
Neo-adjuvant chemotherapy
Before the surgery to improve operability and chances of cure i.e. to shrink the tumour prior to removal
Palliative chemotherapy
Used for symptom control not cure, advanced cancer
Difference between targeted and non-targeted chemotherapy
Chemotherapy can be broadly divided into targeted and non-targeted. Non-targeted chemotherapy agents block the stages of the cell cycle, inhibiting DNA replication and mitosis. Targeted chemotherapy can differentiate between cancerous and non-cancerous cells.
Types of non-targeted anicancerous agents
Alkylating agents, Platinum agents, Antimetabolites, Anthracyclines, Anti-microtubule agents.
Cancer- Alkylating agents
For example, Cyclophosphamide. Covalently bind to Alkyl groups in the nucleotide Guanine, induces crosslinking DNA. The inhibits DNA replication and transcription so the cell undergoes cell cycle arrest and apoptosis.
Examples of Alkylating agents (cancer)
- Cyclophosphamide-leukaemias, lymphoma and solid tumours
* Chlorambucil-lymphoma and chronic leukaemias
Cancer- Platinum agents
For example, Cisplatin. Most widely used chemotherapy drugs. They bind to the nucleotide Guanine causing cross linked DNA which inhibits DNA replication and transcription. The cell undergoes cell cycle arrest and apoptosis. Connected to the Platinum you have two highly reactive Chlorine groups which interact with other proteins responsible for replication. They cause DNA protein cross links, induces stress mechanisms within the cells and the cells undergo apoptosis.
Examples of Platinum agents
- Carboplatin- ovarian and lung cancer
* Cisplatin- testicular, lung, cervical, bladder and head/neck cancer
Cancer- Antimetabolites
For example Methotrexate. They interfere with the normal cell metabolism of nucleic acids. Methotrexate inhibits the production of Pyrimidines and Purines by inhibiting the enzyme DHFR. Decreases nucleotides inhibiting DNA replication
Normal production of Purines and Pyrimidines
Dietary folate is converted to FH2 which is converted by DHFR (Dihydrofolate reductase) into FH4. This is then converted to Purines or can be converted to Pyrimidines by Thymidylate synthase.
Example of antimetabolites
- Methotrexate-acute leukaemia, non-Hodgkin’s lymphoma and solid tumours
- 5-Fluorouracil- GI and breast cancer
Anthracyclines
For example Doxorubicin. These are anti-tumour antibiotics.
1) Inhibits Tropoisomerase 2 (Its normal role is to induce double stranded breaks to relax and stabilise DNA replication). This will prevent DNA relaxation and DNA reannealing which will create multiple DNA double strand breaks.
2) It can indirectly inhibit Helicase by intercalating into DNA and stabilising it, preventing it from being separated.
3) Produce reactive oxygen species which induce DNA/cell damage and apoptosis.
Examples of Anthracyclines
- Doxorubicin- leukaemia, lymphoma and breast cancer
- Epirubicin- breast cancer
- Idarubicin- haematological cancer
Cancer- anti microtubule agents
Disrupts the microtubule spindle which is required for effective separation of the chromatids. Microtubules are also important for cell migration (prevent metastasis), however this will cause a range of side effects as it disrupts normal cell function. Can be separated into Vinca Alkaloids and Taxanes. Affects mitosis but not DNA replication
Types of anti-microtubule agents
- Vinca alkaloids- for example Vinicristine, prevents tubulin assembly, cant assemble the mitotic spindle. Chromatids cant separate, they experience cell arrest during anaphase.
- Taxane- for example Doxetaxel (breast and lung cancer). Prevents tubulin disassembly so you cant contract the mitotic spindle. Experience cell cycle arrest at the M phase checkpoint in Anaphase and die.
Signs and symptoms of the menopause
- Hot flushes / night sweats
- Menstrual irregularities- can be heavier bleeding which occurs more regularly
- Difficulty sleeping
- Reduced sex drive (libido)
- Recurrent urinary tract infections (UTIs), increased frequency of urination, urinating at night
- Poor memory and concentration
- Headaches
- Mood changes, such as low mood or anxiety
- Palpitations
- Joint stiffness, aches and pain- Osteoporosis is the progressive loss of bone mass which alters bone microarchitecture, greater susceptibility to breaks. Osteopenia causes thinning of the bones.
- Reduced muscle mass
What causes the Menopause
Oestrogen withdrawal
Menopause- what causes vaginal dryness, itching or discomfort during sex
Its caused by atrophy, inflammation and reduced collagen. Thinning of the mucosal layer and thickening of the stroma. Thins out the vagina, making it more delicate. Reduction in oestrogen causes a loss in lubrication. There can be a reduction in elasticity making movement difficult and can cause bleeding and itch.
Average age of the menopause
52
Menopause- Vasomotor symptoms
Vasomotor symptoms i.e. hot flushes can by triggered by alcohol/caffeine, exercise and environmental temp changes. Due to the effect of fluctuating oestrogen levels on the thermoregulatory centre. Change to blood flow, blood might shift to the skin causing a feeling of warmth and flushing. Dilation in small blood vessels.
Diagnosing the Menopause
In women over 45 the diagnosis of menopause does not need additional lab tests. Its 12 months since last menstrual period when the women is not using hormonal contraception, diagnosed retrospectively. Usually a transitional stage with irregular cycle and vasomotor symptoms, this is the peri-menopause stage.
How many menstrual cycles in a womens life
400-500
How to measure a womens ovarian reserve
Using an ultrasound or measuring FSH and AMH, will indicate a womens fertility
Premature menopause
Amenorrhoea in women <40
Causes of Premature menopause
- Insidious (Premature Ovarian Insufficiency)- chromosomal abnormalities i.e. Turners syndrome, Fragile X, Autoimmune, infection (TB, malaria, mumps)
- Iatrogenic-surgical menopause, consequence of cancer treatment (chemotherapy, radiotherapy)
Diagnosis and investigations into the premature menopause
- Diagnosis based on symptoms and menstrual irregularities
- Endocrine test for FSH / LH / oestradiol- should be 6 weeks
- Cause investigated with genetic screening, pelvic USS, infection screen i.e. mumps, thyroid function
- Led by specialist reproductive endocrinologist
Treatment for the premature menopause
- HRT- replacement rather than in addition, wont be exposed to the side effects older women have with increased levels of hormones.
- Cardiovascular health
- Skeletal health
- Reproductive wishes
Hormonal status- post menopause
- FSH levels continually increase as it tries to stimulate the ovary to release oestrogen
- As without folliculogenesis there is no increase in oestrogen.
- There is no feedback loop or inhibin so FSH levels remain high, as no follicles remain then FSH cannot induce folliculogenesis. LH levels no longer surge but they also increase
- High FSH, LH. Low Oestrogen.
Complications of HRT
- IHD i.e. angina/MI
- CVD
- VTE
- Untreated hypertension
- History of breast cancer
- Untreated endometrial hyperplasia (pre-cursor to cancer)/endometrial cancer
- Undiagnosed vaginal bleeding
Deciding to go on HRT
HRT increases cardiovascular disease risk and breast cancer. Someone with a lot of risk factors for these conditions or who has already had them, might decide not to go on HRT. The risk with HRT to background risk can be multiplicative not adative. Important to know individual risk
General advice for the menopause
- Life-style= avoidance of triggers (alcohol, caffeine), healthy BMI, exercise (can reduce vasomotor symptoms)
- Natural remedies- vitamins, can contain phito-oestrogen
- Vaginal moisturisers and lubricants
Benefits of HRT
- Symptom control- vasomotor, vaginal dryness
- Reduces risk of osteoporosis
- Improves muscle mass
- Menstrual cycle control
What makes up HRT
Can either be Oestrogen, Progesterone or Testosterone
Nuclear/genomic action of HRT
- Oestrogen can bind to either ERα or Erβ receptors on the cell membrane
- Oestrogen then diffuses into the cytoplasm
- Binds to receptor in cytoplasm
- Translocated to nucleus
- Alters gene transcription
- Creates new mRNA
- Translation of new proteins through gene transcription
- Proteins produced depend upon the tissue type
How HRT affects the bones
In the bones oestrogen prevents bone reabsorption. In the Myocardium oestrogen reduces inflammation, in skeletal muscle it regenerates muscle fibres. Can also help with insulin resistance preventing diabetes.
Risks of HRT
Breast cancer, heart disease, pulmonary embolism stroke
When to use local or systemic HRT
If you only have Urogenital symptoms (vagina, bladder) then apply local oestrogen, if you have additional symptoms use systemic oestrogen.
Systemic HRT
• Without uterus- use Oestrogen (typically oral)
• With Uterus- Oestrogen and Progesterone
Using Progesterone reduces the risk of endometrial hyperplasia
Sequential and continuous HRT
Sequential HRT- continuous oestrogen, sequential progesterone. Causes a withdrawal bleed, like a period. Given for perimenopause. If you gave the continuous preparation it would cause irregular periods
Continuous HRT- continuous oestrogen and progesterone which means there is no bleed, given post menopause
HRT- testosterone preparation
Helps improve libido, energy, mood and concentration. Can be prepared in a gel, patch or implant. Can be particularly beneficial in younger women.
SERM
Selective oestrogen receptor modulator. Non- hormonal drugs that help to increase oestrogen in some tissues but not others, and so there can be used to prevent the osteoporosis risk. Used when HRT cannot be used
Pharmacokinetics of HRT
- First line therapy is normally oral
- Easy and convenient
- First pass effect
- Has to pass through the liver, and so some of it is metabolised, and so a higher dose needs to be given if the liver is overactive
- Shouldn’t be given to people with liver disease or people taking enzyme inducing medication, as this will increase breakdown lowering the concentration.
- Contra-indications- Nausea, and other GI symptoms
- Patients with a history of VTE should not be given the oral preparation
- Fluctuations in the hormone levels
- Patch/Gel/Implant are considered if taking the medication orally isn’t working or advisable
Types of HRT given
Can also be given in gel, patch or implant. The patch can be in any location except the breast. The implant can be subdermal or intrauterine.
Side effects of HRT
Caused by oestrogen- Fluid retention, Nausea, Headaches, Breast tenderness and Leg cramps
Caused by Progesterone- Irregular bleeding, PMS, bloating and depression
How to reduce side effects of HRT
- Breast symptoms - Reduce Dose
- GI symptoms - take with food, to alleviate the symptoms
- Change type of hormone, or the brand of the hormone
- Change route of administration
How long should you take HRT for
For people who had a premature menopause they should HRT till they are 52. There is an increase risk of side effects with duration of use, because of the increase in background relative risk with age. This should be considered when deciding to stop HRT. Normally a gradual stop to prevent reflux symptoms (dose reduction).
HRT alternatives
- Selective oestrogen receptor modulator (SERM)
- Selective serotonin reuptake inhibitors (SSRI’s)- i.e. venlafaxine
- Serotonin-norepinephrine reuptake inhibitors (SNRIs) i.e. paroxetine
- Antihypertensive (alpha agonist) i.e. clonidine
- Antiepileptic i.e. Gabapentin
Menopause and contraception
If last menstrual period is before 50 take contraception for 2 more years. If its after 50 take it for 1 more year. Contraception can help with the symptoms of menopause. Thought the chance of pregnancy is small you can still get it
Risk factors for a mother having a baby with a neural tube defect
- They have already had a baby with a neural tube defect
- They or their partner have a close relative born with a neural tube defect
- They have type 1 (insulin dependent) diabetes (not gestational diabetes)
- They are obese, or take certain anti-epileptic medications, especially those containing sodium valproate or valproic acid
Why is chemotherapy given in cycles and combinations
Cycles- stops cancer cells from recovering and regrowing
Combinations- targeting multiple signalling pathways makes it less likely for resistance to develop.
What causes the side effects in chemotherapy
It inhibits cell division in all rapidly dividing cells
1) Hair/skin- allopecia, rash
2) Mucosal linings- nausea, ulcers, constipation, diarrhoea
3) Gonadal function
4) Bone marrow- reduced erythrocytes, leukocytes and platelets
Anticancer drugs- Hormone antagonists
Stops cancers that develop in hormone sensitive tissue. Their growth may be inhibited by estrogen, progesterone, androgen receptor antagonists that stop the production of hormones
Tamoxifen
1) SERM – Selective Estrogen Receptor Modulator
2) Anti-proliferative in breast tissue
3) Used in breast cancer treatment and prevention
4) 75% of breast cancer are Estrogen Receptor (ER) Positive
5) Competitive inhibibitor of Estradiol binding to the Estrogen receptor, Tamoxifen binds to the ER to form a dimer
Protein kinase inhibitors i.e. Imatnib
Inhibits an oncogenic protein kinase (BCR-ABL) which causes chronic myeloid lukaemia. This protein kinase is only found in cancer cells and promotes cell proliferation. Imatinib inhibits ATP binding of BCR-ABL oncoprotein, preventing phosphorylation and activation of downstream substrates.
Protein kinase inhibitors i.e. Imatnib
Inhibits an oncogenic protein kinase (BCR-ABL) which causes chronic myeloid lukaemia. This protein kinase is only found in cancer cells and promotes cell proliferation. Imatinib inhibits ATP binding of BCR-ABL oncoprotein, preventing phosphorylation and activation of downstream substrates.
Cancer treatment- Immunotherapy
Activates the bodies own immune system to recognise and kill cancer cells by removing immune checkpoint inhibitors.
Pd-1 receptor antagonists (Pembrolizumab)
Immunotherapy- a group of checkpoint inhibitors for the treatment of multiple solid cancers
