L17 Clinical Pharmacology of Anticancer Agents Flashcards
List all available classes of anticancer agents based on their biochemical classification.
1) Alkylating Agents
2) Enzyme Inhibitors
- Topoisomerases I Inhibitors
- Topoisomerases II Inhibitors (i.e. etoposide & anthracyclines)
3) Antimetabolites
- Folate Antagonists
- Purine Analogues
- Pyrimidine Analogues
4) Anti-microtubules
- Vinca Alkaloids
- Taxanes
5) Endocrine Therapies
6) Targeted Therapies (i.e. small molecule drugs & mAb)
7) Immunotherapies
8) Miscellaneous
Briefly explain the MOA of all available classes of anticancer agents based on their biochemical classification.
1) Alkylating Agents:
- Directly acts on existing DNA structures via monoalkylation, intercalation, or inter-/intra-strand crosslinking
2) Enzyme Inhibitors
- Disruption of transcription and translation of DNA via inhibition of topoisomerases I/II
3) Antimetabolites
- Interferes production of DNA as analogues / antagonists
4) Anti-microtubules
- Inhibit polymerisation of tubules or depolymerisation of microtubules in cellular division
5) Endocrine Therapies
- Slows/stops tumour cells dependent on hormones for growth
6) Targeted Therapies
- Exert specific effects on tumour cells that prevent them from either entering cell cycle or target signals that trigger cancer growth, metastasis & immortality, resulting in slowing/halting tumour growth.
7) Immunotherapies
- Uses immune system to fight cancer via helping them to recognise & attack tumour cells
Name an alternative classification of anticancer agents and explain how the classification is done.
Based on cell cycle classification.
Each of the transitions in the cell cycle (G1 > S > G2 > M > G1) requires the activation of cyclin-dependent kinases (CDKs).
1) Cell-cycle specific agents
- Preferentially kill proliferating cells (e.g. 5-FU)
- Cell-cycle phase-specific agents preferentially kill in specific phases of cell cycle.
2) Cell-cycle non-specific agents
- Kill both normal & malignant cells to same extent
Describe the mechanism of action of cell-cycle (phase) specific anticancer agents.
Preferentially kills proliferating cells
Toxic to PROPORTION OF CELLS in the particular phase in cell cycle these agents are active in.
- Toxicity is the greatest during the S phase in DNA synthesis.
What is one administration consideration to account for when administering a cell-cycle (phase) specific anticancer agent?
Administer as a continuous IV infusion to allow greater exposure to more cells in specific cycle based on MOA.
- Due to MOA of killing proportion of cells, rather than an absolute number of cells.
Describe the mechanism of action of cell-cycle non-specific anticancer agents.
Exert cytotoxic effect throughout cell cycle, including resting phase.
Cell kill is PROPORTIONAL TO DOSE!!
Name some classes of anticancer agents that are considered cell-cycle non-specific anticancer agents.
1) Alkylating agents & Nitrosoureas
2) Anthracyclines (i.e. Topoisomerases II inhibitors)
3) Antitumour Abx (i.e. immunotherapy)
Unlike other drugs, toxicities of anticancer drugs are at _____ & _____ at therapeutic doses. They can be classified as _____.
Increased frequencies & increased severity.
1) Acute vs delayed / chronic
2) Self-limiting vs permanent
3) Mild vs potentially life-threatening
Differentiate between acute and delayed toxicities of anticancer drugs.
Acute:
- Due to inhibition of cell division
- Happens during administration or w/in days of Tx
- Most susceptible in tissues with fast renewal of cell populations e.g. GIT mucosal cells, skin/hair & bone marrow
Delayed:
- Occurs months to years after Tx
- Possible irreversible effects include infertility & secondary malignancies from anticancer Tx
- Drug-specific toxicities:
(a) Anthracycline-induced cardiac toxicity: lifetime cumulative dose-dependency
(b) Methotrexate-induced pneumonitis after prolonged low-dose MTX Tx
Which class of anticancer drugs is known to be the largest class that was first introduced clinically? Name five clinically relevant examples from this class.
Alkylating agents:
1) Nitrogen mustards: Cyclophosphamide & ifosfamide
2) Platinum analogues: Carboplatin (1st), cisplatin (2nd) & oxaliplatin (3rd)
Explain the MOA of alkylating agents.
1) Common molecular MOA of alkylation of DNA
- However, each agent greatly differs in PK, lipid solubility, chemical reactivity and properties of membrane transport.
2) Major cytotoxic effect results from the formation of a positively charged carbonium ion which binds to electron-rich nucleophilic sites on DNA (intended) & biological molecules
- E.g. Amines, hydroxyl, phosphates, sulfhydryl groups
- N7 atom of guanine is highly susceptible to alkylation & accounts for 90% of alkylated sites in DNA
- Other sites include N1 & N3 of adenine, N3 of cytosine & O6 of guanine
3) Cytotoxic effects result from one of the following:
- Inhibition of DNA replication and transcription
- Mispairing of DNA
- Strand breakage
4) In general, alkylating agents do NOT show cross-resistance!!
Which site of DNA is highly susceptible to alkylation by alkylating agents for the treatment of cancer?
N7 of guanine
Accounts for 90% of alkylated sites in DNA
Other sites include N1 & N3 of adenine, N3 of cytosine & O6 of guanine
Describe the possible toxicities associated with the use of alkylating agents.
1) General dose-limiting toxicity (DLT): Myelosuppression
- Usually neutropenia w/ a nadir of 6-10 days & recovery in 14-21 days
- EXCEPT nitrosourea class; nadir of 28-35 days & recovery of at least 42 days
2) Other toxicities: (due to cell-cycle non-specific MOA)
- Mucositis
- Chemotherapy-induced nausea & vomiting (CINV)
- Neurotoxicity
- Alopecia
3) Long-term toxicities:
- Pulmonary fibrosis
- Infertility
- Secondary leukemias (peak incidence approx 4 years post-Tx)
Explain the MOA of cyclophosphamide.
Prodrug activated by CYP2B6 in liver to give:
- 4-hydroxycyclophosphamide (active) and
- Aldophosphamide (active tautomer of 4-hydroxycyclophosphamide)
Aldophophamide can be further metabolised to give:
- *Acrolein (primary cytotoxic metabolite) and
- Phosphoramide mustard (cytotoxic) via non-enzymatic pathway OR
- Carboxyphosphamide (inactive) via aldehyde oxidase
Describe the PK of cyclophosphamide.
A: F > 75%, rapidly absorbed in 1-2h (peak); taken w/ food to decrease GI upset or empty stomach
D: Plasma protein binding = 12-14% (unchanged drug); 67% (total plasma alkylating metabolites)
M: Primarily CYP2B6 metabolism / bioactivation; prone to CYP2B6 inhibition & induction
E: Primarily excreted in urine as metabolites; renal dose adjustment required
Which metabolite of ifosfamide is responsible for causing dose-dependent hemorrhagic cystitis?
Acrolein
Name some indications in which cyclophosphamide is used in the treatment of cancer.
Lymphomas
Breast cancer
Bone marrow transplant
List the toxicities associated with the use of cyclophosphamide in anticancer Tx.
1) Dose-related CINV
- Emetogenic potential: > 1g high moderate; < 1g low moderate
2) SIADH -> Hyponatremia (rare)
3) Hemorrhagic cystitis (rare unless at high doses)
- Due to cytotoxic acrolein
- Prevented with co-administration of mesna
4) Cardiac dysfunction (rare unless at high doses)
Name some indications in which ifosfamide is used in the treatment of cancer.
Testicular cancer
Diffuse large B-cell lymphoma
Explain the MOA of ifosfamide.
Analogue of cyclophosphamide & a prodrug activated by CYP3A4 in liver to give:
- 4-hydroxyifosfamide (active) and
- Aldoifosfamide (active tautomer of 4-hydroxyifosfamide)
Aldoifosfamide can be further metabolised to give:
- *Acrolein (primary cytotoxic metabolite) and
- Isophosphoramide mustard (cytotoxic)
Cytotoxic MOA primarily through DNA crosslinks by alkylation of isophosphoramide mustard at guanine N7 positions.
- Formation of inter- and intra-strand DNA crosslinks results in cell death.
- Cell-cycle specific BUT cell-cycle phase non-specific
Describe the PK of ifosfamide.
D: Negligible plasma protein binding
M: Primarily CYP3A4 metabolism / bioactivation; prone to CYP3A4 inhibition & induction
E: Excreted in urine as 14-50% unchanged & 15-41% as metabolites; renal dose adjustment required
What are some administration issues to consider when administering ifosfamide?
1) MUST administer mesna!!
- Vigorous hydration w/ 1.5-2L of normal saline pre- and post-hydration
- Due to high risk of haemorrhagic cystitis!
- Daily dose of mesna suggested to be 60% of total daily dose of ifosfamide!!
- Prior to initiation, give mesna = 20% of total daily ifosfamide dose & subsequently dose another at 4h & 8h upon start of IV infusion
2) Encourage patients to increase oral fluid intake!
3) Use with caution in elderly patients & renally impaired pt.!
- Increase infusion time to manage nephrotoxicity
4) Avoid concurrent administration of CNS active drugs to minimise neurotoxicity.
5) Decrease dose or discontinue Tx w/ onset of symptoms
List the toxicities associated with the use of ifosfamide in anticancer Tx.
1) CINV
2) Neurotoxicity (CNS)
- Presented as hallucinations, confusion, somnolence
- Smx usually begin 2-5 days after start of ifosfamide
- MOA: Accumulation of chloroacetaldehyde (tautomer of 4-hydroxyifosfamide) due to MAO metabolism of ifosfamide
- Avoid concurrent administration of CNS active drugs!!
3) Nephrotoxicity
- Use w/ caution in elderly patients!
- Caution w/ renal dysfunction
- Increase infusion time as management
4) Dose-related haemorrhagic cystitis
- Due to cytotoxic acrolein
- Prevented with COMPULSORY co-administration of mesna
What is a possible antidote that can be used in the event of ifosfamide dose toxicity?
Methylene blue
- Inhibits monoamide oxidase (MAO) metabolism of ifosfamide into chloroacetaldehyde.
