Week 9: Drugs for Cancer (Chapter 21 and 33)
Cancer:
Cancer cells manifest uncontrolled proliferation, invasiveness, the ability to metastasize
and/or infiltrate normal tissue and loss of function due to lack of capacity to differentiate.
Benign tumours manifest only uncontrolled proliferation.
Alterations in DNA underlying cancerous change:
o Mutation/inactivation of tumour suppressor genes
o Mutation/activation of protooncogenes (code for the growth factor-induced and
apoptotic pathways – control cell cycle and cell proliferation)
Oncogenes code for cancerous changes
o Non-genetic factors: hormonal effects, presence of carcinogens
About chemotherapy:
Background
Most anticancer drugs are cytotoxic; they do not affect the underlying pathogenetic
mechanisms, namely changes in growth factors and/or their receptors in the cell cycle and
apoptotic pathways, in telomerase expression or in tumour-related angiogenesis.
Most are antiproliferative, acting primarily on dividing cells and have no specific inhibitor
effect on invasiveness, loss of differentiation or tendency to metastasize.
These cytotoxic drugs affect rapidly dividing normal cells, depress bone marrow, impair
healing, depress growth, cause sterility and hair loss and be teratogenic, cause nausea and
vomiting and detrimental effects on mucous lining of the GI tract.
Cancer chemotherapy: use of chemicals to selectively kill actively dividing cancer cells
o But in a tumour, only a proportion of cells are in this phase, so a single
chemotherapy dose only kills some cells.
Exploits differences between healthy and cancer cells
Kills cancer cells and minimises toxicity to healthy cells
Chemotherapy regime should balance toxicity and anti-cancer effect
Most chemotherapy is given in cycles lasting 3-4 weeks, with 4-6 cycles making up one
course of treatment. Cells that were not actively dividing in the first cycle can be killed in the
second cycle.
Normal cells recover more quickly than cancer cells between cycles.
Toxicity of chemotherapy:
Affects tissues with dividing cells e.g. bone marrow and mucous membranes
General side effects of chemotherapeutic agents: hair loss, GI disturbance, nausea,
vomiting, anaemia, immune suppression.
Reduce general side effects by applying chemotherapy in courses, so normal cells can
recover.
Side effect Treatment Details
Non-specific
Nausea and Cocktail of antiemetics: D2 antagonists Given before
vomiting* (chlorpromazine) [causes tremor side effect], chemotherapy
5HT3 antagonist, H1 antagonist
Hair loss Wig, cold cap Using a cold cap
will reduce the
, amount of drug
reaching the
hair.
GI disturbance e.g. Antacids e.g. sucralfate, proton pump inhibitors Symptomatic
peptic ulcer, GI (omeprazole), fluids, Na2CO3 tablets treatments
bleeding
(epithelium is highly
replicating)
Leukopenia Immunostimulants, G-CSF, antibiotics, Given >24hrs
(neutropenia) experimental stem cell treatments after
chemotherapy
because BM
cells will be
actively dividing
due to G-CSF
and hence
become a target
for cytotoxic
drugs.
Anaemia/low G-CSF, blood/platelet transfusions To increase
platelets erythrocytes
Specific
Haemorrhagic Mesna Binds acrolein
cystitis to deactivate it
(cyclophosphamide)
Dose-related Experimental therapy But regular ECG
cardiomyopathy monitoring
(doxorubicin)
*Chemotherapy is the application of toxins, which enter circulation, travel to the BBB, where the
chemoreceptor trigger zone (CTZ) is located. Upon stimulation of the CTZ, neurons and receptors
involved in the vomiting neurocircuit are activated. These include dopamine via D2 receptors,
serotonin via 5HT3 receptors, Substance P via NK1 receptors, and histamine via H1 receptors.
[GT epithelium cell damage = enterochromaffin cells in stomach make serotonin = stimulates
afferent neurons and enters circulation -> BBB -> CTZ stimulated -> neurons + receptors.]
After chemotherapy, some patients suffer from leukopenia (low WBC count) and increased
risk of infection due to bone marrow toxicity and suppression.
o Anaemia – fatigue
o Low platelets – bleeding
o Low leukocytes – risk of infection (neutropenic sepsis or opportunistic infections)
Gastrointestinal toxicity:
o Nausea and vomiting
o Oral mucositis
o Treatment: anti-emetic therapy, fluids, mouthwashes
o 5’-FU, capecitabine and irinotecan can damage intestinal mucosa and cause
diarrhoea.
Cardiotoxicity:
o Doxorubicin and daunorubicin are anthracycline antineoplastic antibiotics used for
leukaemias, lymphomas and other cancers
Cancer:
Cancer cells manifest uncontrolled proliferation, invasiveness, the ability to metastasize
and/or infiltrate normal tissue and loss of function due to lack of capacity to differentiate.
Benign tumours manifest only uncontrolled proliferation.
Alterations in DNA underlying cancerous change:
o Mutation/inactivation of tumour suppressor genes
o Mutation/activation of protooncogenes (code for the growth factor-induced and
apoptotic pathways – control cell cycle and cell proliferation)
Oncogenes code for cancerous changes
o Non-genetic factors: hormonal effects, presence of carcinogens
About chemotherapy:
Background
Most anticancer drugs are cytotoxic; they do not affect the underlying pathogenetic
mechanisms, namely changes in growth factors and/or their receptors in the cell cycle and
apoptotic pathways, in telomerase expression or in tumour-related angiogenesis.
Most are antiproliferative, acting primarily on dividing cells and have no specific inhibitor
effect on invasiveness, loss of differentiation or tendency to metastasize.
These cytotoxic drugs affect rapidly dividing normal cells, depress bone marrow, impair
healing, depress growth, cause sterility and hair loss and be teratogenic, cause nausea and
vomiting and detrimental effects on mucous lining of the GI tract.
Cancer chemotherapy: use of chemicals to selectively kill actively dividing cancer cells
o But in a tumour, only a proportion of cells are in this phase, so a single
chemotherapy dose only kills some cells.
Exploits differences between healthy and cancer cells
Kills cancer cells and minimises toxicity to healthy cells
Chemotherapy regime should balance toxicity and anti-cancer effect
Most chemotherapy is given in cycles lasting 3-4 weeks, with 4-6 cycles making up one
course of treatment. Cells that were not actively dividing in the first cycle can be killed in the
second cycle.
Normal cells recover more quickly than cancer cells between cycles.
Toxicity of chemotherapy:
Affects tissues with dividing cells e.g. bone marrow and mucous membranes
General side effects of chemotherapeutic agents: hair loss, GI disturbance, nausea,
vomiting, anaemia, immune suppression.
Reduce general side effects by applying chemotherapy in courses, so normal cells can
recover.
Side effect Treatment Details
Non-specific
Nausea and Cocktail of antiemetics: D2 antagonists Given before
vomiting* (chlorpromazine) [causes tremor side effect], chemotherapy
5HT3 antagonist, H1 antagonist
Hair loss Wig, cold cap Using a cold cap
will reduce the
, amount of drug
reaching the
hair.
GI disturbance e.g. Antacids e.g. sucralfate, proton pump inhibitors Symptomatic
peptic ulcer, GI (omeprazole), fluids, Na2CO3 tablets treatments
bleeding
(epithelium is highly
replicating)
Leukopenia Immunostimulants, G-CSF, antibiotics, Given >24hrs
(neutropenia) experimental stem cell treatments after
chemotherapy
because BM
cells will be
actively dividing
due to G-CSF
and hence
become a target
for cytotoxic
drugs.
Anaemia/low G-CSF, blood/platelet transfusions To increase
platelets erythrocytes
Specific
Haemorrhagic Mesna Binds acrolein
cystitis to deactivate it
(cyclophosphamide)
Dose-related Experimental therapy But regular ECG
cardiomyopathy monitoring
(doxorubicin)
*Chemotherapy is the application of toxins, which enter circulation, travel to the BBB, where the
chemoreceptor trigger zone (CTZ) is located. Upon stimulation of the CTZ, neurons and receptors
involved in the vomiting neurocircuit are activated. These include dopamine via D2 receptors,
serotonin via 5HT3 receptors, Substance P via NK1 receptors, and histamine via H1 receptors.
[GT epithelium cell damage = enterochromaffin cells in stomach make serotonin = stimulates
afferent neurons and enters circulation -> BBB -> CTZ stimulated -> neurons + receptors.]
After chemotherapy, some patients suffer from leukopenia (low WBC count) and increased
risk of infection due to bone marrow toxicity and suppression.
o Anaemia – fatigue
o Low platelets – bleeding
o Low leukocytes – risk of infection (neutropenic sepsis or opportunistic infections)
Gastrointestinal toxicity:
o Nausea and vomiting
o Oral mucositis
o Treatment: anti-emetic therapy, fluids, mouthwashes
o 5’-FU, capecitabine and irinotecan can damage intestinal mucosa and cause
diarrhoea.
Cardiotoxicity:
o Doxorubicin and daunorubicin are anthracycline antineoplastic antibiotics used for
leukaemias, lymphomas and other cancers
