Cancer Chemotherapy Flashcards
What is a tumour?
Types?
Any abnormal proliferation of cells
Benign = stays in its original location
Malignant = tumours are capable of invading surrounding tissue or invading the entire body
Causes of cancer?
Environmental exposure - sun, tobacco, radiation
Viruses
Oncogenes
Tumour suppressor genes
Cancer txs?
Surgery
RT - mainly possible when tumour remains localised at the time of diagnosis
Chemotherapy - once cancer metastases chemo is required (often combined with RT to allow surgical resection to occur)
What are chemo drugs based on?
Chemical composition
Route of administration
Type of cancer targeted
Side effects
Primary induction chemotherapy - what does it treat?
For advanced cancer with no alternative tx - can be curative in only a small subset of pts (e.g. Hodgkins and non-hodgkin’s lymphoma in adults or lymphoblastic leukaemia in children)
Neoadjuvant chemotherapy - what does it treat?
In pts with localised cancer for which alternative local therapies e.g. surgery exists but are less than completely effective
Adjuvant chemo - what is it for?
As an adjuvant to local therapy such as surgery or radiation
Effective in prolonging both disease free and survival of pts with a different type of cancer (breast, colon gastric or non-small lung cancer)
What is the main goal of antineoplastic agents?
To eliminate cancer cells without affecting normal tissues
But it affects normal tissues as well as malignancies so aim for a favourable therapeutic index
What is a therapeutic index?
The lethal dose of a drug for 50% of the population divided by the minimum effective dose for 50% of the population
How to achieve a cure with chemotherapy?
A total cell kill must be tried
Early diagnosis and early instruction of tx
Combination chemotherapy
Intermittent regimens
Adjuvant and neoadjuvant chemo occasionally
What is the log-kill hypothesis?
Chemotherapeutic agents kill a constant proportion of tumour cells, rather than a constant number of cells, after each dose
Solid cancer tumours - have a low growth fractions = respond poorly to chemo and need to be removed by surgery
Disseminated cancers - have a high growth fraction and generally respond well to chemo
What cancers respond well to chemo?
Disseminated cancers - have a high growth fraction
What cancers respond poorly to chemo?
Solid cancer tumours - low growth fractions
What are cell cycle specific drugs?
Drugs that exert their action on cells traversing the cell cycle
What are cell cycle non-specific drugs?
Drugs that sterilize tumour cells whether they are cycling or resting in the G0 (resting phase) compartments
Examples of cell cycle specific and cell cycle non-specific drugs?
CCS:
- Antimetabolites (S phase) (5-fluorouracil, methotrexate)
- Taxanes (M phase) (paclitaxel)
- Vinca Alkaloids (M phase) (vinblastine)
- Antimicrotubule inhibitor (M phase) (Ixabepilone)
- Antitumous antibiotics (G2-M phase) (bleomycin)
CCNS
- Alkylating agents (lomustine)
- Antitumour antibiotics (mitomycin)
- Camptothecins (topotecan)
- Platinum analogs (cisplatin, carboplatin)
- Anthracyclines (doxorubicin)
What do alkylating agents do?
Form highly reactive carbonium ion = transfer alkyl groups to neucleopholic sites on DNA bases =
- Cross linkage
- Abnormal base pairing
- DNA strand breakage = reduces cell proliferation
Negatives of alkylating agents?
Carcinogenic in nature, can increase risk of 2ndry malignancies
Immunosuppressant action
Bone marrow depression
Nausea and vomiting
Most of adverse effects are dose related and occur primarily in rapidly growing tissues
What do alkylating agents treat?
A wide variety of haematologic and solid tumours (ovarian cancer, brain tumours)
Alkylating agents - Busulfan uses?
Chronic myelogenous leukaemia and other leukaemia, lymphomas and myeloproliferative disorders
Controls tumour burden but cannot prevent transformation or correct cytogenic abnormalities
Alkylating agents - Lomustine uses?
Requires biotransformation to agents that have alkylating or carbamoylating activities
Can cross blood brain barrier, mainly treats brain tumours
Alkylating agents - decarbazine uses?
Malignant melanoma Hodgkin lymphoma Sarcoma Islet cell carcinoma of the pancreas Mainly given IV, is bioactivated in liver
Alkylating agents resistance?
Increased activity of DNA repair enzyme
Increase metabolic inactivation of the drug
Decrease influx of the drug
How to platinum analogues exert their cytotoxic effects?
Form highly reactive platinum complexes
= Intrastrand and interstrand cross-link
= DNA damage
= Inhibits cell prolif
Platinum analogues (CCNS) features?
e.g. cisplatin
Highly bound to plasma protein
Highly concentrated in kidney, intestines and testes
Mainly used for testicular, ovarian cancer and solid tumours (oesophagus, gastric)
Poorly penetrates BBB
Extensively cleared by kidney and slowly excreted in urine
Adverse effects - vomiting, nephrotoxicity, peripheral neuropathy
What do antimetabolites do? Examples?
Act on metabolism of proliferating cells.
Interfere with DNA and RNA growth (s phase)
Folate antagonist (i.e. Methotrexate) Purine antagonists (i.e. 6 Mercaptopurine) Pyrimidine antagonist (i.e. 5 Fluorouracile)
Antimetabolites - Methotrexate features?
Binds to the active catalytic site of dihydrofolate reductase = inhibits synthesis of tetrahydrofolate = interferes with the formation of DNA, RNA and key cellular proteins
Poor brain penetration, remains unchanged in urine
Actions of methotrexate? Adverse effect?
Cytotoxic, mainly on bone marrow
Immunosuppressive, preventing clonal expansion of B and T lymphocytes
Anti-inflammatory
Adverse effect - megablastic anaemia, leukopenia, alopecia, nephropathy
Antimetabolites - 6 Mercaptopurine features?
Mainly used in childhood acute leukaemia
Inactive in its parent form, must be metabolised in its active form
Inhibit synthesis of purine nucleotides = metabolites alter the synthesis and function of RNA and DNA
Does not cross BBB
Adverse effects of 6 mercaptopurine?
Nausea, vomiting, fatigue, stomach/abdominal pain, fever
Antimetabolites - 5 fluoronuracil features?
Used in stomach, colon, breast, ovaries, liver and skin cancer.
Inactive in its parent form, requires activation via a series of
enzymatic reaction to ribosyl and deoxirybosil nucleotide metabolites
in order to interfere with DNA’s synthesis.
Extreme short half life (5-10 min).
Antimetabolites - 5 fluoronuracil adverse effects?
nausea, vomiting, headache, mood disorder, cardiotoxicity, GI ulceration and bleeding, vein pigmentation. Local pain, burning, dermatitis.
Vinca alkaloids act by?
inhibiting tubulin proliferation = disrupt assembly of
microtubules = mitotic arrest in metaphase, bringing cell
division to a halt = CELL DEATH.
Natural product
Vinca alkaloids - Vincristine features?
Used for childhood cancers - Hodgkin’s and non-Hodgkin’s lymphoma,
lymphosarcoma.
Main dose-limiting toxicity is neurotoxicity, usually
expressed as peripheral sensory neuropathy, autonomic nervous system
dysfunction, constipation and ataxia.
Vinca alkaloids - Vinblastine - what does it treat and what are its adverse effects?
Used in Hodgkins disease and other lymphoma, breast and testicular
cancer. Main adverse effects include bone marrow suppression, nausea,
vomiting and alopecia.
What are taxanes?
Alkaloid esters
How do taxanes act?
Enahnce tubulin polymerization
This promotion of
microtubules assembly occurs in absence of microtubules-associated
proteins and guanosine triphosphate, resulting in inhibition of mitosis
and cell division
Taxanes - Paclitaxel features?
Used in a broad range of solid tumour (i.e. advanced breast cancer,
ovarian cancer , head and neck, prostate and bladder cancer).
Extensively metabolized in the liver with 80% of the drug excreted in
faeces. Dose reduction is required in patients with liver diseases.
Taxanes - Paclitaxel adverse effects?
nausea, vomiting, hypersensitivity,
myelosuppression, and hypotension.
How do antitumour antibiotics work?
Bind to DNA through intercalation between specific bases =
- Block RNA, DNA synthesis
- DNA strand scission
- Interfere with cell replication
What are cancer antibiotics from?
Streptomyces
Antitumour antibiotics - Doxorubicin (Anthracycline) features?
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.
Antitumour antibiotics - Mitomiycin C (CCNS) features?
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.
Best available drug to use in combination with radiotherapy to attack hypoxic tumour cells
Antitumour antibiotics - Bleomycin (CCS) features?
It is a small peptide, binds to DNA = 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. Advantage can be given SC, IM or IV.
Eliminated via renal excretion. Can lead to Pneumonitis, hyperpigmentation and spares bone marrow.
What do glucocorticoids treat?
Acute leukaemia and lymphomas due to their marked lympholytic effect
What do estrogens do?
Physiological antagonists of androgens, so used to antagonize the effect
of androgens in androgen dependent prostate cancer
What do estrogens antagonists do?
Used in breast cancer. Selective Estrogen Receptor (ER) Modulators, or ER down regulator.
Adverse effects of estrogens antagonists?
hot flushes, vomiting, menstrual
irregularities.
When are bone metastases a common occurrence?
In pts with advanced solid tumours
Metastasis to skeleton occurs in pts with multiple myeloma and metastatic breast, prostate and thyroid cancers
What is spread of cancer to bone associated with?
Pain, hypercalcemia, anaemia
Increased infec risk
Compression of spinal cord/or nerve roots
Decreased mobility and skeletal fracture
What do bisphosphonates do?
- Slow down the rate of growth of bone crystal and their resolution
- Reduce morbidity from bone metastasis by reducing skeletal events.
- Lower calcium levels.
- After IV administration approximately 25–40% is excreted by the kidney, and the remainder is taken up by bone.
- Poor oral bioavailability
- As they bind to calcium in the diet can cause gastrointestinal toxicities such as nausea, vomiting, indigestion, oesophagitis, and diarrhoea.
What do drug combinations provide?
Maximal cell kill within a range of toxicity tolerated by the host for each drug without compromising the dosing
Broader range of interactions between drugs and tumour cells
Has potential to prevent or slow the subsequent development of cellular drug resistance
What to take into account when combining drugs?
Efficacy: only drugs known to be somewhat effective when used alone
Toxicity: can’t overlap between drugs.
Optimum scheduling: Optimal dose and schedule of each drug should
be used and drug combination should be given at consistent intervals.
Mechanisms of interaction: Maximal effect is achieved with a clear understanding of biochemical, molecular and pharmacokinetics
mechanisms and interaction between the individual drugs.
Avoidance of arbitrary dose changes: risk of decreasing effectiveness and risk to destroy the ability of the combination to cure disease in a given patient.
Drug resistance features?
Critical in chemo
Some tumours have primary resistance
Acquired resistance when exposure to an anticancer agent
Can be highly specific to a drug - based on genetic changes of a tumour cell with amplification and expression
Multi-drug resistant phenotype can occur = enhanced drug efflux and reduced intracellular accumulation
Other mechanisms:
- Drug not metabolised to active form = inactive drug = drug target is increased = alternative biochemical pathway increased
