Cytotoxic Drugs Flashcards
What are the different parts of the cell cycle?
G0 to G1
G1 to S
S to G2 (DNA synthesis)
G2 to M
What are the general characteristics of cell cycle specific chemo agents?
Tumour specific
Duration of exposure more important than dose
What are examples of cell cycle specific chemo agents?
Antimetabolites; impairs nucleotide synthesis/ incorporation
Mitotic spindle inhibitors
What are examples of antimetabolites?
Methotrexate: Inhibits dihydrofolate reductase 6-Mercaptopurine/ cytosine arabinoside: Incorporated into DNA Hydroxyurea: Impaired deoxynucleotide synthesis
What are examples of mitotic spindle inhibitors?
Vinca alkaloids; vincristine/ vinblastine
Taxotere (taxol)
What are the general characteristics of non-cell cycle specific agents?
Non-tumour specific; damage normal stem cells
Cumulative dose more important than duration
What are examples of non-cell specific agents?
Alkylating agents
Platinum derivatives
Cytotoxic antibiotics
What are examples of alkylating agents?
Chlorambucil/ melphalan
Bind covalently to bases of DNA and produce DNA strand breaks by free radical production
What are examples of platinum derivatives?
Cisplatin
Carboplatin
What are examples of cytotoxic antibiotics?
Anthracyclines; daunorubicin/ doxorubicin/ idarubicin
DNA intercalculation, impair RNA transcription, form free radicals via strand breaks in DNA
What are the immediate side effects to cytotoxic drugs?
Bone marrow suppression
Gut mucosal damage
Alopecia
What are examples of drug specific side effects?
Vinca alkaloids; neuropathy
Anthracyclines; cardiotoxicity
Cisplatin; nephrotoxicity
What are some specific side effects to alkylating agents?
Infertility
Secondary malignancy
What is the basis of combo chemo administration?
Non-cross resistant drug combos
Non-overlapping toxicity spectra
Additive/ synergistic mechanisms of action
Why will chemo fail?
Slow tumour doubling time
Drug resistant mechanisms
What are some common drug resistant mechanisms that cancers will adopt?
Decreased drug accumulation; MDR-1
Altered drug metabolism; cyclophosphamide
Increased DNA repair; cisplatin
Altered gene expression; reduced topoisomerase 2
What limited intensive chemo?
Myelosuppression
What can be done to overcome the myelosuppression associated with intensive chemo?
Haematopoietic growth factors
Combine myelosuppressive/ non-myelosuppressive agents
Intensify doses of active drugs (log-linear tumour kill) + stem cell rescue
What are sources of stem cells for transplantation?
Blood vs bone marrow
Autologous
Allogeneic - sibling or unrelated
What are the basic steps for stem cell transplantation?
Myeloablative therapy
Stem cell reinfusion
Bone marrow regeneration
What is the specific treatment used for CML?
Targeted therapy with tyrosine kinase inhibitors
What occurs in the G1 phase of the cell cycle?
Cell increases in size
Cellular contents duplicate
What occurs in the S phase of the cell cycle?
DNA replication
What occurs in the G2 phase of the cell cycle?
Cell prepares for division
What occurs in the M phase of the cell cycle?
Mitosis followed by cytokinesis
Formation of 2 identical daughter cells
What are the phases in the M cycle?
Prophase Metaphase Anaphase Telophase Cytokinesis
What occurs in prophase?
Nucleolus disintegrates
Nuclear membrane breaks down
Spindle fibres appear
What occurs in metaphase?
Chromosomes align at the metaphase plate
What occurs in anaphase?
Centromeres divide
Sistem chromatids move to opposite poles
What occurs in telophase?
Nuclear membrane reforms
Chromosomes decondense
Spindle fibres disappear
What regulates the cell cycle?
Checkpoints
What checkpoint is located at G1?
Restriction point (R)
What will activation of the checkpoint result in?
Increased p53 production
p53 is a tumour suppressor gene that stops the cell cycle and starts repair mechanisms for damaged DNA
What is the function of Rb in the cell cycle?
Restricts the ability of a cell to progress from G1 to S
CDK (cyclin dependent kinase) will phosphorylate it making it unable to restrict cell proliferation
What cyclin is present at the G2 checkpoint?
Cyclin B
CDK 1
What cyclin is present at the start of G1?
Cyclin D
CDK4
What cyclin is present at the end of G1?
Cyclin E
CDK 2
What cyclin in present in S?
Cyclin A
CDK2