Cancer Chemotherapy Flashcards
Causes of cancer
Environmental exposure
Viruses
Oncogenes
Tumour suppressor genes
Cancer is
What is a tumour
Benign behaviour
Malignant behaviour
What do tumours arise from
Second leading cause of mortality
Continuous uncontrolled growth of cells
Any abnormal proliferation of cells
Stay confined to original location
Capable of invading surrounding tissue or invading whole body
Any type of cell in body and classified by that
Treatments
When is radiotherapy possible
When is chemo required and what is it combined with
Surgery
Radiotherapy - when tumour is localised at diagnosis
Chemotherapy - once cancer metastasises so is required for effective cancer management
Combined with radiotherapy to allow resection to take place
Surgery and radio therapy are usually more possible when
tumour remains localised at the time of diagnosis
Chemotherapy drugs
Vary based on
More than 100 used today
- chemical composition
- route of administration - type of cancer targeted
- side effects
Types of chemo
Primary induction chemo
Neoadjuvant chemo
Adjuvant chemo
Primary induction chemo
Effectiveness?
Administered in patients with advanced cancer for which no alternative treatment exists.
Can be curative in only a small subset of patients who present with advance disease. (i.e. Hodgkin’s and non-Hodgkin’s lymphoma in adults or lymphoblastic leukemia in children).
Neoadjuvant chemo
in patients with localised cancer for which alternative local therapies, e.g. surgery, exist but which are less than completely effective.
Adjuvant chemo
alternative to?
Effective in?
An adjuvant to local therapy such as surgery or radiation. Is effective in prolonging both disease-free and overall survival in patients with different type of cancer (i.e. patients with breast, colon gastric or non-small lung cancer)
Main goal of antineoplastic agents
Eliminate cancer cells without affecting normal tissues
All cytotoxic drugs affect normal tissues as well as malignancies
Therapeutic dose
Formula
A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50).
LD50/ED50
Log-kill hypothesis
- Chemotherapeutic agents kill a constant PROPORTION of tumour cell population (first order kinetics), rather than a constant NUMBER of cells, after each dose
- Solid cancer tumours – generally have a low growth fractions thus respond poorly to chemotherapy and in most cases need to be removed by surgery
- Disseminated cancers- generally have a high growth fraction and generally respond well to chemotherapy
Drugs can be
CCNS can
Cell cycle specific (exert actions on cells traversing cell cycle) and cell cycle non specific
sterilize tumour cells whether they are cycling or resting in the G0 compartments.
CCNS are
Alkylating agents/Antitumour antibiotics/Camptothecins/Platinuum analogues/Anthracyclines
Carcinogenic in nature and can increase the risk of secondary malignancies
Due to systemic effect
Can sterilise tumour cells whether they are cycling or in resting phase
Reduces cell proliferation
Alkylating agents - used to
- treat a wide variety of haematologic and solid tumour (i.e. ovarian cancer, brain tumours)
- immunosuppressant action
• Most of the adverse effects are generally dose-related and occur
primarily in rapidly growing tissues
• Bonemarrowdepression
• Nausea and Vomiting. Antiemetics are often given prior and after alkylating agents dosing
Alkylating agents examples
Busulfan (Alkyl sulfuantes)
- Mainly used for chronic myelogenous leukemia and other leukemias, lymphomas and myeloproliferative disorders.
- Controls tumour burden but can not prevents transformation or correct cytogenic abnormalities.
Lomustine (Nitrosoures)
- Requires biotransformation to agents that have alkylating or carbamoylating activities.
- Can cross the blood brain barrier, mainly used to treat brain tumours.
Decarbazine (Triazenes)
- Used in the treatment of various cancers, among them malignant melanoma, Hodgkin lymphoma, sarcoma, and islet cell carcinoma of the pancreas. Mainly given IV, is bioactivated in the liver.
Issues with CCNS - resistance
Mechanism (3 methods)
- Increased activity of DNA repair enzyme
- Increase metabolic activation of the rug
- Decrease influx of the drug
Platinum analogues (are a type of?) e.g (most common)
Cisplatin mechanism
CCNS
Cisplatin
Mechanism unclear
Exert cytotoxic effect similar to alkylating agents
Form highly reactive platinum complexes
Intra strand and inter strand cross linkages
DNA damage
Reduce cell proliferation
Cisplatin features
Used for? But poor at?
cleared by?
Adverse effects?
Highly bound to plasma proteins
Highly conc in kidney, intestines and testes
Used for these cancers
Poorly penetrates blood brain barrier
Cleared by kidney and slowly excreted in urine
Vomiting, nephrotoxicity, peripheral neuropathy and ototoxicity
Taxanes
Type of
Mechanism - when does it occur
Example - used when, where is it metabolised, dose reduction when? Adverse effects
CCS
Alkaloid ester
Enhance tubulin polymerisation (occurs in absence of appropriate proteins)
Inhibition of mitosis and cell division
Paclitaxel
- broad range of solid tumours
- in liver 80% excreted in faeces - liver disease
- nausea, emesis, hypersensitivity, myelosuppression, hypotension
Anti tumour antibiotics
Type of?
Mechanism
Examples
CCNS Bind to DNA through intercalation between specific bases - block synthesis of RNA, DNA or both - scission of DNA strand - interfere with cell replication 1. doxorubicin 2. mitomycin 3. bleomycin
Doxorubicin is a type of…
Used against?
Used with?
How?
Anthracycline
- Mainly used against breast, ovary, testicles, stomach, thyroid and bladder cancer. - Often used in combination with other anticancer drugs. - Generates free radicals leading to cardiotoxicity.
Mitomycin
Type
Used in?
Mechanism
Used in combination with?
CCS
Highly toxic
- used in resistant cancers of stomach, colon and rectum.
- Its metabolite act like alkylating agent that cross-links DNA.
- It is active in all phases of the cell cycle.
- It is the best available drug to use in combination with radiotherapy to attack hypoxic tumour cells
Bleomycin
Type
Features
Mechanism
Used for?
Administration?
Excretion?
Adverse effects
CCS
- small peptide
- binds to DNA resulting in single- and double-strand breaks, leading to inhibition of DNA biosynthesis
- Causes accumulation of cells in G2 phase.
- Used for lymphomas, head and neck cancer.
- can be given SC, IM or IV.
- Eliminated via renal excretion.
- Pneumonitis, hyperpigmentation and spares bone marrow.
Hormones and antagonists
3 types
Glucocorticoids
Oestrogen
Oestrogen antagonists
Bisphosphonates
When does MS occur
Common in patients with advanced solid tumours and metastasis to skeleton
Myeloma, MS breast, prostate and thyroid
Spread of cancer to bone is associated with
- pain,hypercalcemia,anemia
- increased risk of infection,
- compression of the spinal cord and/or nerve roots
- decreased mobility and skeletal fracture (catastrophic)
Role of bisphosphonates
What happens after admin
Disadvantages
- Slow down the rate of growth of bone crystal and their resolution by inhibiting osteoclasts and promote apoptosis
- Reduce morbidity from bone metastasis by reducing skeletal events.
- Lower calcium levels
25-40% excreted by kidney and rest taken up
Poor oral bioavailability
Gastrointestinal toxicities such as nausea, vomiting, indigestion, oesophagitis and diarrhoea
Drug resistance is
What is ACQUIRED resistance
Specific to?
Multidrug resistance results in
Other mechanisms of resistance
- Critical in chemo because some tumours can exhibit PRIMARY resistance
- develops in response to exposure to a GIVEN anticancer agent
A single drug, due to single change in genetic machinery of a given tumour cell
Enhanced drug efflux and reduced intracellular accumulation of broad range of unrelated cancer agents
Drug not activated, Drug not metabolised to active form, drug target increased, alternative pathway activated instead
To achieve a chemotherapeutic cure…
TOTAL CELL KILL
Early diagnosis and early institution of tx
Combination chemotherapy
Intermittent regimens
Adjuvant and neoadjuvant chemotherapy occasionally
CCS categories
Antimetabolites/Taxanes/Vinca Alkaloids/Antimicrotubule inhibitor/Antitumous antibiotics
Alkylating agents CCNS - mechanism
Highly reactive carbonium ion
Transfers alkyl group to nucleophilic sites on DNA bases
Affects cell proliferation
Antimetabolites
Are a type of
What do they act on? Mechanism
3 types?
CCS
Intermediary metabolism of proliferating cells
Interfere with DNA and RNA growth by substituting normal building blocks of RNA and DNA during S phase
Folates antagonist
Purine antagonists
Pyrimidine antagonist
Methotrexate
Is an
Negatives
Where does it act?
Adverse effects
Antimetabolite
Binds to active catalytic site of dihydrofolate reductase
inhibits synthesis of tetrahydrofolate
interferes with formation of DNA, RNA and key cellular proteins
Poor brain penetration, remains in tissue longer than folate prolonging inhibitor effect, remains unchanged in urine.
Cytotoxic, mainly on bone marrow
Immunosuppressive, preventing clonal expansion of B&T lymphocytes
Anti-inflammatory
Megaloblastic anaemia
Leukopenia
Alopecia
Nephropathy
Purine antagonist e.g
Used for
In order to work?
Mechanism
Negatives
Adverse effects
6 mercaptopurine
Childhood acute leukaemia
Must be metabolised into active form
Inhibits synthesis of purine nucleotides
Metabolites alter synthesis and function of RNA and DNA
Does not cross BBB
Nausea, vomiting, fatigue stomach/abdo pain, fever
pyramidine antagonist e.g
Acts on?
What required?
Half life?
Adverse effects
5 fluorouracil
Stomach, colon, breast, ovaries, liver and skin cancer
Activation via enzymatic reaction
Extreme short half life (5-10 mins)
Nausea, vomiting, headache, mood disorder, cardiotoxicity, GI ulceration and bleeding, vein pigmentation, local pain, burning, dermatitis
Vinca alkaloids
CCS
Natural alkaloid products derived from Vinca Rosea
Inhibit tubular proliferation
Disrupt assemble of microtubules
Mitotic arrest in metaphase
Cell division ceases –> cell death
Vinca alkaloids e.gs and uses (2)
Vincristine
childhood cancers, H&NH lymphoma, lymphosarcoma
= neurotoxicity
Vinblastine
Hodgkin’s disease and other lymphoma
Bone marrow suppression, nausea, vomiting and alopecia
Glucocorticoids
Used in? Due to?
Used in acute leukaemia and lymphomas
Lymphocytic effect
Oestrogens
Used as?
Antagonists of androgen so antagonise effect of androgens in androgen dependent prostate cancer
Oestrogen antagonists
Used in?
Adverse effects
Breast cancer
Oestrogen receptor DOWN regulator
Hot flushes, emesis, menstrual irregularities
