Cytotoxic Drugs Flashcards
Never make treatment worse than the disease
T
What is remission?
When the disease is no longer detectable, but it is still there
In what stages does do cells differentiate/remain quiescent?
G0/G1
What can cytotoxic drugs be classified as?
Either cell cycle specific or non-cell cycle specific
What are the characteristics of cell cycle specific drugs?
- Relatively tumour specific.
* DURATION of exposure more important than dose.
Name 2 cell cycle specific drugs.
- Antimetabolites.
* Mitotic spindle inhibitors.
How do antimetabolites work?
By impairing nucleotide synthesis/incorporation
Give the most common example of an antimetabolite?
Methotrexate
How does methotrexate work?
Inhibits dihydrofolate reductase.
Name 3 antimetabolites, and how each of these works.
- Methotrexate - inhibits dihydrofolate reductase.
- 6-Mercaptopurine / Cytosine arabinoside / Fludarabine - incorporated into DNA.
- Hydroxyurea - Impaired deoxynucleotide synthesis (ribonucleotide reductase).
What enzyme is responsible for:
i) folate metabolism?
ii) nucleotide synthesis?
iii) unwinding DNA?
i) Dihydrofolate reductase.
ii) Ribonucleotide reductase/adenosine deaminase.
iii) Topoisomerase II (non-cell-cycle specific).
What do mitotic spindle inhibitors arise from? Give an example of one.
Plant derivatives – vinca alkaloids (vincristine) / vinblastine
- Taxotere – Taxol
What are the characteristics of non-cell cycle specific agents?
- Non-tumour specific; damage normal stem cells.
* Cumulative dose more important than duration.
Give examples of 3 non-cell cycle specific agents.
- Alkylating agents.
- Platinum derivatives.
- Cytotoxic antibiotics.
Give examples of alkylating agents.
- Chlorambucil
* Melphalan
How do alkylating agents work?
Bind covalently to bases of DNA (adducts), producing DNA strand breaks (mutation) by free radical production.
BASICALLY, interrupt DNA
Give examples of platinum derivatives.
- Cis-platinum
* Carboplatinum
Give examples of cytotoxic antibiotics.
- Anthracyclines: daunorubicin/doxorubicin/idarubicin
Explain how cytotoxic antibiotics work.
- DNA intercalation: reversible.
- Impairs RNA transcription.
- Strand breaks in DNA (free radicals).
Outline the general side effects of cytotoxic drugs.
Affects rapidly dividing organs:
- Bone marrow suppression (neutropenic sepsis is a major concern)
- Gut mucosal damage.
- Hair loss (alopecia).
What is the long term side effects of alkylating agents?
Infertility, secondary malignancy.
What is the long term side effects of anthracyclines?
Cardiomyopathy
What is the main side effect associated with cis-platinum?
Nephrotoxicity
What is the main side effect associated with Vinca alkaloids?
Neuropathy
Why does chemotherapy fail?
- Slow tumour doubling time.
- Tumour ‘sanctuaries’ e.g. tumour cells can evade the immune system in areas like the testis and brain (because of BBB and blood-testis barrier).
Suggest specific mechanisms of drug resistance.
- Decreased drug accumulation; MDR-1 / PGP
- Altered drug (pro-drug) metabolism: cyclophosphamide
- Increased DNA repair; cis-platinum resistance
- Altered gene expression: reduced topoisomerase II
What is intensifying chemotherapy limited by?
Myelosuppression
How can myelosuppression be overcome?
- Use haematopoietic growth factors.
- Combine myelosuppressive/non-myelosuppressive agents.
- Intensify doses of active drugs (log-linear tumour kill) + stem (progenitor) cell rescue.
How can a source of stem cells for transplantation be reached?
Either through BLOOD or BONE MARROW
What are the options for patient source of stem cells?
- Autologous. (from pt themselves)
* Allogenic – sibling, unrelated.
What chromosome is chronic myeloid leukaemia associated with?
The Philadelphia chromosome
What is the result of the philadelphia chromosome?
A balanced translocation between chromosomes 9 and 22
