Cytotoxic and Supportive Therapy Flashcards
(22 cards)
Loeb’s rules of therapeutics?
- If the intervention is having a beneficial effect, continue
- If the intervention is having too many adverse effects, stop
- If you do not know what to do, do nothing
- Never make the treatment worse that the disease
Pathway that therapeutic interventions often take?
ADD IMAGE
Remission - no evidence of disease; if the patients continues to be in remission for a certain period, they may be cured
Progression through the cell cycle?
Interphase:
• G1 - metabolic changes occur that prepare the cell for division, e.g: protein synthesis
• S phase (9-12 hours) - DNA synthesis replicates the genetic material
• G2 - metabolic changes assemble the cytoplasmic materials necessary for mitosis and cytokinesis
M phase (1-2 hours):
• Mitotic phase (nuclear division)
• Cytokinetic phase (cytoplasmic division)
NOTE - cells in G1 can cycle into G0, which is a quiescent phase where the cells are not actively preparing to divide
Classification of cytotoxic drugs, with relation to the cell cycle?
Cell-cycle specific
Non-cell cycle specific
General characteristics of cell-cycle specific cytotoxic agents?
Relatively tumour-specific
The duration of exposure is more important than the dose
Types of cell-cycle specific agents?
Anti-metabolites - impair nucleotide synthesis / incorporation
Mitotic spindle inhibitors
Examples of anti-metabolites?
Methotrexate - inhibits dihydrofolate reductase, thus interfering with folate metabolism and DNA synthesis
6-Mercaptopurine / cytosine arabinoside / fludarabine - incorporated into DNA
Hydroyurea - inhibits ribonucleotide reductase and thus there is impaired deoxynucleotide synthesis
Examples of mitotic spindle inhibitors?
Vinca alkaloids, e.g: vincristine / vinblastin
Taxotere (Taxol)
General characteristics of non-cell cycle specific agents?
Non-tumour specific, so normal stem cells are also damaged
The cumulative dose is more important than duration of therapy
Types of non-cell cycle specific agents?
Alkylating agents, e.g: chlorambucil / melphalan - bind covalently to DNA bases and produce DNA strand breaks, due to free radical production
Platinum derivatives, e.g: Cis-platinum / carboplatin
Examples of non-cell cycle specific agents?
Cytotoxic antibiotics, like the anthracyclines, e.g: daunorubicin, doxorubicin, idarubicin
These antibiotics have a few mechanisms:
• Inhibit DNA & RNA synthesis by intercalating base pairs of the DNA/RNA strand
• Impair RNA transcription
• Create DNA strand breaks due to the production of free radicals
Immediate general side effects of cytotoxic drugs?
Immediate side effects are the ones that affect rapidly dividing organs:
• Bone marrow suppression
• Gut mucosal damage
• Alopecia
Examples of drug specific side effects of cytotoxic drugs?
Vinca alkaloids - neuropathy
Anthracyclines - cardiotoxicity
Cis-platinum - nephrotoxicity
Long-term side effects of cytotoxic drug groups?
Alkylating agents:
• Infertility
• Secondary malignancy
Anthracyclines:
• Cardiomyopathy
Features of combination chemotherapy?
Non-cross resistant drug combinations
Non-overlapping toxicity spectra
Additive / synergistic mechanisms of action
Why does chemotherapy fail?
Slow tumour doubling time
Tumour sanctuaries, e.g: blood-brain barrier, blood-testis barrier
Drug resistance
Mechanisms of drug resistance?
Decreased drug accumulation, e.g: MDR-1 / PGP
Altered drug (pro-drug) metabolism, e.g: cyclophosphamide
Increased DNA repair, e.g: cis-platinum resistance
Altered gene expression, e.g: reduced topoisomerase II
Limitations on intensifying chemotherapy?
Limited by myelosuppression
How can myelosuppression, a limiting factor on intensifying chemotherapy, be overcomes?
- Use haematopoietic growth factors
- Combine myelosuppressive / non-myelosuppressive agents
- Intensify doses of active drugs (log-linear tumour kill) + stem (progenitor) cell rescue
Sources of stem cells for transplantations:
Tissue source:
• Blood versus bone marrow
Patient source:
• Autologous
• Allogeneic - sibling or unrelated
Process of progenitor cell transplantation?
- Blood / bone marrow cell collection, autologous or allogeneic
- Myeloablative therapy
- Progenitor cell re-infusion
- Bone marrow regeneration
Targeted therapy available for CML?
Tyrosine kinase inhibitors, e.g: imatinib
