Cancer Pharmacology (part I) Flashcards
What are alkylating agents?
Highly reactive organic molecules which “alkylate” DNA by
interacting with nucleophilic groups in the DNA molecule. This disrupts normal DNA causing induction of
apoptosis.
What part of the cell cycle do alkylating agents target?
Alkylating agents are phase non-specific. Cells must be cycling to be killed, but the drugs are active at any point in the cycle
What type of response curve do alkylating agents have?
Alkylating agents have a linear response curve
- higher dose => more cells killed
What are common side effects of alkylating agents?
- Nausea
- Marrow suppression
- Mutagenesis
- Secondary carcinogenesis
What is mechlorethamine (nitrogen mustard)?
Mechlorethamine was the first chemotherapeutic agent
How is nitrogen mustard administered?
Nitrogen mustard is usually given via IV infusion but also topical to treat T-cell neoplasms
Why does mechlorethamine not require dose adjustment in renal or hepatic failure?
Mechlorethamine is rapidly regraded by NON-ENZYMATIC hydrolysis and therefore does not require dose adjustment in renal or hepatic failure
What are the major side effects of mechlorethamine?
- Nausea
- Vomiting
- Alopecia
- Myelosuppression
- Secondary cancers (especially leukemia, lymphoma, MDS)
What is Cyclophosphamide?
- A chemical derivative of mechlorethamine
- The most widely used of the alkylating agents – used in a variety of hematologic and solid tumors.
How is cyclophosphamide administered?
May be given either IV (used for higher doses) or orally.
How is cyclophosphamide activated and eliminated?
- Must be activated by the hepatic p450 system.
- Eliminated by hepatic metabolism (75%) of kidneys (25%).
What is a unique side effect of cyclophosphamide and how is it caused?
- Hemorrhagic cystitis.
- This is caused by the metabolite acrolein that is secreted in the urine.
- This can be prevented by aggressive hydration or (more commonly) MESNA (2-mercaptoethane sulphonate) that binds and inactivates acrolein in the urine.
What is cisplatin?
Cisplatin is a bifunctional alkylating agent that is a commonly used analogue
How does cisplatin work?
Cisplatin enters cells by passive diffusion then becomes ionized
- It binds to DNA to form interstrand and intrastrand cross links
- Cell cycle specific
What types of cancers is cisplatin used in?
- Lung
- Breast
- Ovarian
- Head and Neck cancers
What are the major side effects of cisplatin?
- Renal insufficiency
- Neuropathy
- Both are reversible
What is a “secondary” malignancy?
- Secondary malignancy are a side effect of drugs used to treat a primary or initial cancer
What is a common phenomena associated with secondary malignancy?
- Polycythemia vera
- Leukemia is also a side effect
Treatment of lymphoma leads to risk of what secondary condition?
- Treatment of lymphoma with intense therapy has lead to approximately 10% of patients being at risk of secondary leukemia and breast cancer
- Risk is greatly increased when alkylators and XRT are combined
What are the most common secondary malignancies?
- AML
- MDS
- These are usually highly resistant to any therapy
How does chemotherapy cause emesis?
- Enterochromaffin cells release serotonin in response to emetic chemotherapy agents
- When serotonin binds its receptor it acts on the vagus nerve leading to emesis/nausea
What is Ondansetron (Zofran)?
Ondansetron is a selective serotonin receptor blocking agent that is though to block 5HT stimulation of the vagus nerve
- It may also work by blocking CNS serotonin receptors
- HELPS TO PREVENT VOMITING AND NAUSEA
How is Ondansetron administered?
Ondansetron is given IV or po about 1/2 hour before chemo
What can Ondansetron be combined with for maximal benefit?
- Can be combined with steroids for maximal benefit
What is aprepitant?
Aprepitant, a nerokinin1 agonist that blocks substance P binding is a new antiemetic that can be combined with 5-HT inhibitors.
What are antimetabolite agents?
- Broadly antimetabolite agents inhibit the normal metabolic functions of cells
- Most antimetabolite drugs are targeted to DNA or RNA synthesis
- These agents commonly resemble normal metabolic intermediates
Which phase are antimetabolite agents specific for?
Most antimetabolites are specific for the S phase
How should antimetabolites be administered?
Antimetabolites should be given by continuous IV infusion or hyper fractionated IV bolus
Which cells are particularly sensitive to antimetabolites?
– Rapidly cycling normal cells (bone marrow and gut epithelium) are often highly sensitive to these agents
What is methotrexate?
Methotrexate is a direct descendant of aminopterin
- this is a an analogue of folic acid and inhibits DHFR by competitive inhibition
How is methotrexate administered?
- Low dose => oral immuno-suppresion
- High dose => IV
What cancers are methotrexate commonly used for?
- Lymphoma
- Braset cancer
- Head and neck cancer
- Lung cancer
How is methotrexate given to treat CNS cancers?
Methotrexate is give intrathecally to treat CNS cancers
What are common side effects of methotrexate?
- Marrow suppression
- Gi toxicity (mucositis, diarrhea)
- Renal failure
How is renal failure caused by methotrexate?
- Renal failure is caused by precipitation of the drug in the renal tubules
- Decreased clearance of the drug will increase other side effects
- Urine is alkalinized to prevent this
What is also give with methotrexate to prevent lethal side effects?
- Methotrexate is often given at lethal doses to achieve greater tumor cell kill
- This must be followed by LEUCOVORIN rescue to prevent lethal side effects
How do tumors become resistant to methotrexate?
- Decreased transport
- Gene amplification
- Mutation of DHFR => so that it is no longer inhibited by Methotrexate but is able to utilize folic acid
For what diseases is methotrexate used for immunosuppresion?
Methotrexate is used in rheumatoid arthritis and lupus
What is 5 fluoroucil?
5 Fluoroucil works in the same metabolic pathway as methotrexate
- It inhibits the enzyme thymidylate synthase by a suicide mechanism
For what cancers is 5 fluoroucil used?
- Breast
- GI malignancies
What are the common side effects of 5 fluoroucil?
Bone marrow and GI toxicities
What drug is used to potentiate the action of 5 Fluoroucil (5FU)?
Leucovorin
What is cytarbine?
Cytarbine is the clinically most used member of the nucleoside analogues
- It is the analogue of cytidine with a sugar molecule arabinose
What is the mechanism of action of cytarbine?
- Cytarbine is taken int o the cell and metabolized just as the normal compound
- Once converted to ara-CTP it binds to and competitively inhibits DNA polymerase alpha
- This interferes with DNA replication
- Some of the drug is incorporated into DNA where it acts to slow chain elongation and inhibits DNA ligation
- Once converted to ara-CTP it binds to and competitively inhibits DNA polymerase alpha
At what phase does cytarbine work?
Cytarbine (ara-C) acts on the S phase
What is ara-c most commonly used for?
Cytarbine (ara-c) is most commonly used to treat acute myeloid leukemia (AML)
- It is also used to treat lymphoma
How is ara-c administered?
Ara-c is give by continuous IV for seven days as par tot the AML induction chemotherapy along with Daunarubicin (7+3 regimen)
What are the side effects of cytarbine?
- Marrow aplasia
- GI toxicity
- Alopecia
What dangerous toxicity is associated with high dose ara-c?
HiDAC can cause acute severe cerebellar toxicity
How do topoisomerase inhibitors act?
- Topoisomerases are involved in the unwinding of the supercoiled DNA during DNA replication and mRNA synthesis
- If topoisomeraseas are inhibited DNA damage results and induces apoptosis
What are two major members of anthracycline antibiotics?
- Doxorubicin
- Daunarubicin
How do anthracycline antibiotics work?
- Anthracycline antibiotics consist of a sugar molecule attached to a tetracycline backbone
- The drug is able to intercalate into DNA
- This inhibits DNA replication and mRNA synthesis
- Also inhibits topoisomerase II
How do anthracycline antibiotics act on topoisomerase Ii?
- Anthracyclines stabilize a DNA-TopII intermediate and inhibit relegation of DNA ends
- This results in DNA fragmentation and cell death
What are anthracyclines generally used for?
- Hematologic malignancies
- Breast
- Lung
- GI and GU cancers
How are anthracyclines administered?
IV infusion
How are anthracyclines metabolized?
Hepatic metabolism
- Give decreased dose in liver failure
What are the major side effects of anthracyclines?
- GI
- Marrow
- Cardiac
- Anthracyclines are vesicants (blister agents)
What are the cardiac effects of anthracyclines?
- Anthracyclines produce a cumulative dose dependent cardiomyopathy
- Increased dose leads to increase risk of cardiomyopathy (esp 550mg/m^2)
- The cardiomyopathy is reversible
- Patients are subject tot congestive heart failure and arrhythmias
What are epidophyllotoxins?
- Epidophyllotoxins complex with topoisomerase II and cause DNA breaks
What dose limiting toxicity is associated with epidophyllotoxins?
- Neutropenia
What are the main drugs in the epidophyllotoxin class?
- PV-16
- Etoposide
What is VP-16 used to treat?
- Testicular
- Ovarian
- Lung
- Lymphoid cancers
What are topoisomerase I inhibitors?
- Topotecan/irinotecan are topoisomerase I inhibitors which inhibit the enzymes ability to relegate DNA during replication
- This results in double strand breaks which are strong activators of DNA damage dependent apoptosis pathways
-
- This results in double strand breaks which are strong activators of DNA damage dependent apoptosis pathways
What phase of the cell cycle do topoisomerase I inhibitors work?
S phase
What cancers are treated with topoisomerase I inhibitors?
- Lung
- Ovarian
- Colorectal
What is a lethal side effect of topoisomerase I inhibitors (topotecan/irinotecan)?
Diarrhea
