Cytotoxic Chemotherapy Flashcards
in which phases of the cell cycle do cells proliferate?
S, G2 and M
in what phases of the cell cycle do cells differentiate or remain quiescent?
G0
G1
when does DNA synthesis occur?
S phase
classification of cytotoxic drugs?
cell cycle specific
non-cell cycle specific
general characteristics of cell cycle specific agents?
tumour specific (relatively) duration of exposure more important than dose
types of cell cycle specific agents?
antimetabolites (impair nucleotide synthesis/incorporation)
mitotic spindle inhibitors
examples of antimetabolites?
methotrexate (inhibits dihydrofolate reductase)
6-mercaptopurine/cytosine arabinoside/fludarabine (incorporated into DNA)
hydroxyurea (impaired deoxynucleotide synthesis - ribonucleotide reductase)
why are dihydrofolate reductase and ribonucleotide reductase targeted?
dihydrofolate reductase = folate metabolism
ribonucleotide reductase = nucleotide synthesis
both involved in formation of nucleotide pool leading to new DNA strand synthesis
what enzyme unwinds DNA?
topisomerase II
examples of mitotic spindle inhibitors?
vinca alkaloids (vincristine/vinblastine)
taxotere (taxol)
both are plant derivatives
general characteristics of non-cell cycle specific agents?
non-tumour specific so damage normal stem cells
cumulative dose more important than duration
examples of non-cell cycle specific agents?
alkylating agents (e.g chlorambucil/melphalan) platinum derivatives (cis-platinum/carboplatin) cytotoxic antibiotics (anthracyclines)
how do alkylating agents work?
- bind covalently to bases of DNA (adducts)
- produce DNA strand breaks (Mutation) by free radical production
how do cytotoxic antibiotics work?
DNA intercalation (reversible) impairs RNA transcription strand breaks in DNA (free radicals)
general imediate side effects of cytotoxic drugs?
(affects rapidly dividing organs)
bone marrow suppression
gut mucosal damage
hair loss
drug specific side effects?
vinca alkaloids = neuropathy
anthracyclines = cardiotoxic
cis-platinum = nephrotoxic
long term side effects of alkylating agents?
infertility
secondary malignancy
long term side effects of anthracyclines?
cardiomyopathy
what is combination chemotherapy?
combination of non-cross resistant drugs with non-overlapping toxicity spectra
results in additive/synergistic mechanisms of action
why can chemo fail?
slow tumour doubling time
tumour sanctuaries
can have drug resistant mechanisms (decreased drug accumulation, altered drug metabolism, increased DNA repair, altered gene expression)
intensifying chemo is limited by what?
the myelosuppression caused
how is myelosuppression due to chemo overcome?
use of haematopoietic growth factors
combine myelosuppressive and non-myelosuppressive agents
intensify doses of active drugs + stem cell rescue
sources of stem cells for transplantation?
tissue source (blood vs bone marrow) patient source (autologous or allogenic - sibling or unrelated match)
steps in progenitor/stem cell transplant?
blood/bone marrow cell collection > myeloablative therapy (destroy immune system) > reinfusion of progenitor/stem cells > bone marrow regenerates
