7. Anti-Cancer Drugs Flashcards
Classification of anticancer agents
Cytotoxic drugs:
- alkylating agents
- platinum based drugs
- anti-metabolites
- microtubules inhibitors
- cytotoxic antibiotics
- topoisomerase inhibitors
PACMAT
Platinum based drugs, Alkylating agents and Cytotoxic antibiotics → phase non-specific
Targeted therapy:
- Tyrosine kinase inhibitors
- Receptor tyrosine kinase inhibitors
- Immunotherapy: therapeutic antibodies, T-cell immunotherapy
Mechanism of cytotoxic drugs
- Greatest selectivity against proliferating cells
- By interrupting cellular process e.g. DNA replication, microtubule formation, which are crucial for cell division
- Functions through inducing apoptosis
How do cytotoxic drugs reduce cancer load
Via log-kill hypothesis
- follows first order kinetics → a fixed percentage of tumour cells per cycle
- one-log drug kills 90%, two-log drug kills 99%, three-log drug kills 99.9%
Advantages of chemotherapy combinations
- Maximal cell kill within range of toxicity for each drug
- Provides synergy between drugs in heterogenous tumour cell populations
- Prevent or slow development of drug resistance
Common chemotherapy side effects
Common acute toxicity:
- myelosuppression
- nausea, vomiting, gastrointestinal effects
- mucous membrane ulcerations
- alopecia
Late organ toxicity:
- cardiotoxicity
- pulmonary toxicity
- nephrotoxicity
- neurotoxicity
- haematological and immunologic impairment
- secondary malignancies
- teratogenicity
- endocrine disruption
- premature menopause, infertility
MOA of alkylating agents
- Phase non-specific
- Reactive alkyl group predominately forms covalent bonds with DNA, cross linking DNA
- Disrupts DNA replication and transcription
- Causes double and single-strand DNA breaks
Examples of alkylating agents
- nitrogen mustard: cyclophosphamide, chlorambucil
- nitrosoureas: carmustine, lomustine, semustine
- alkyl sulfonates: busulfan
- ethylenimines: thiotepa
- triazenes: dacarbazine, procarbazine
MOA of platinum analogue
- Phase non-specific
- DNA adducts leads to intra-strand crosslinks, less so interstrand crosslinks, DNA-protein crosslinks
- Broad spectrum activity: in combination therapy cures testicular cancer
Examples of platinum analogue
cisplatin, carboplatin, oxaliplatin
Adverse effects of platinum analogue
Acute: nausea and vomiting (cisplatin)
Delayed: myelosuppression, nephrotoxicity, peripheral sensory neuropathy (cisplatin and oxaliplatin)
MOA of anti-metabolites
- Cell cycle-specific
- Interfere with 1 or more enzymes or reactions necessary for nucleic acid synthesis
- Restrict the flow of precursors for DNA replication
- Also some incorporated into DNA and produce stress signals
Examples of anti-metabolites
- Methotrexate: inhibits dihydrofolate reductase
2. 5-Fluorouracil: inhibits thymidylate synthase (TS)
MOA of cytotoxic antibiotics
- Phase non-specific
- Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing DNA replication
- Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes
- Inhibition of Topoisomerase II
- Alter membrane fluidity and ion transport
Examples of cytotoxic antibiotics
- Anthracyclines: doxorubicin, daunorubicin, idarubicin, epirubicin
- Others: Mitomycin C, bleomycin
Adverse effects of anthracyclines
- Cardiac toxicity
- Local toxicity
- Nausea, vomiting, alopecia
- Myelosuppressive: dose limiting toxicity
Examples of microtubule inhibitors
- Vinca alkaloids: vinblastine, vincristine, vinorelbine
2. Taxanes: paclitaxel, docetaxel, cabazitaxel
MOA of microtubule inhibitors
- Microtubule inhibitors bind to the beta subunit of tubulin
- Vinblastine and related drugs bind to the polymerising end, preventing elongation of the microtubule
- Paclitaxel stabilises the microtubule, preventing shortening or depolymerisation
Toxicities of microtubule inhibitors
- Hypersensitivity
- Myelosuppression
- Peripheral neuropathy
- Myalgia
- Bradycardia (e.g. taxol)
MOA of topoisomerase inhibitors
Inhibition of type I or type II topoisomerase interferes with transcription and replication of DNA by disruption of appropriate DNA supercoiling
Examples of topoisomerase inhibitors
Type I topoisomerase inhibitors: irinotecan, topotecan
Type II topoisomerase inhibitors: etoposide, teniposide
Toxicities topoisomerase inhibitors
- nausea, vomiting, diarrhoea (irinotecan)
- myelosuppression
- alopaecia (etoposide)
Example of tyrosine kinase inhibitors
Imatinib (Gleevec): used in treatment against Ph+ CML
- BCR-ABL Tyrosine Kinase inhibitors
Erlotinib and Gefitinib: used in treatment against NSCLC
- EGFR tyrosine kinase inhibitors
Alectinib: used in treatment against NSCLC
- ALK tyrosine kinase inhibitors
Types of immunotherapy used in cancer
- Therapeutic antibodies
- neutralising
- antibody-dependent cellular cytotoxicity/ complement-dependent cytotoxicity
- antibody-drug conjugate - T-cell immunotherapy
- Adoptive cell transfer (ACT): engineering patient’s own immune cells to target and kill cancer cells
- Chimeric Antigen Receptor (CAR) T-cells: T cells are engineered to express CARs that recognise tumour cells
- Immune checkpoint inhibitors: CTLA-4 and PD-1
Current challenges in cancer-drug resistance
Intrinsic:
- Tumour type and factors: heterogeneity, mutations, genotypes
- Site: drugs may not cross BBB to reach tumour in the brain → intrathecal injection into spinal canal
- Size: necrotic core, poor vascularisation, diminished growth fraction
Acquired:
Selection of resistant clones → over expression of ABC Transport Proteins
- membrane transport proteins that use ATP to actively efflux toxins and other substances out of the cells
- major mechanism of resistance against anthracyclines
