12_Cell Cycle II Flashcards
list some of the purine antagonists?
- hypoxanthine
- 6-mercaptopurine
- allopurinol
- guanine
- 5-thioguanine
which drugs at at PRPP in the pathway?
(Phosphoribosyl pyrophosphate (PRPP)
- 6-TG: thioguanine
- 6-MP: mercaptopurine
where in the cycle are the purine antagonists act in the biosynthetic pathways?
- acts on rNMP, preventing the conversion into rNDP –> preventing formation of RNA and DNA –> apoptosis
- mercaptopurine and thioguanine: both stops the use of purines;
- prevents the salvage pathway from creating purines
- can’t enter replicatoin–> apoptosis
in which cell cycle phase does the purine antagonists act?
acts on the S phase;
prevents replication/formation of DNA/RNA
mercaptopurine:
admin, indications, mechanism
- admin: oral
- indications:
- acute lymphocytic leukemia
- acute lymphatic leukemia
- mech:
- corresponding nucleotide –> inhibits enzymes involved in purine nucleotide interconversion
- misincorporation into DNA and RNA
mercaptopurine:
toxicity
- acute: no acute toxicity
- delayed:
- myelosuppression
- immunosuppression
- hepatoxicity
thioguanine:
admin, indications, mech
- admin: ORAL
- indications:
- acute adult leukemia
- synergy w/ cytarabine
- mech:
- inhibition of purine nucleotide interconversion
- misincorporation into DNA and RNA
thioguanine:
toxicity
- acute:
- no acute toxicity
- delayed
- myelosuppression
- immunosuppression
- hepatotoxicity
allopurinol:
use
- used to decrease high blood uric acid levels; CO-ADMINISTERED when pt is given purine antagonist drugs
- administered as supportive therapy w/ chemotherapeutic agents:
- prevent gout,
- prevent specific types of kidney stones and
- for the high uric acid levels that can occur with chemotherapy
which drug degrades purine antagonist to act as a cancer chemo drug?
xanthine oxidase;
which acts on allopurinol and hypoxanthine
how is uric acid formed?
HYPOXANTHINE –[xanthine oxidase]–> XANTHINE –[xantine oxidase]–> URIC ACID
by what mechanism does allopurinol help with supportive therapy?
what caution must be noted?
- in chemo, purine analogues are degraded by xanthine oxidase
- ALLOPURINOL administered –> inhibits xanthine oxidase –> to maintain drug concentration
CAUTION: when allopurinol is used, need to LOWER PURINE ANTAGONIST DOSE to PREVENT TOXICITY
list the antimitotic drugs?
are these structural analogs of anything in the cell?
-
EXAMPLES
- vincristine
- vinblastine
- paclitaxel
- docetaxel
- these are NOT structural analogs of anything in the cell; these are different agents
where in the cell cycle do anti-mitotics act?
how does it function?
- **acts during M PHASE
- inhibit polymerization of microtubules by activating the spindle assembly checkpoint (SAC) –> blocking transition from metaphase to anaphase
- cells undergo mitotic arrest
- since the compound disrupts spindle formation and chromosome orientation, –>
- cells remain either in a prolonged arrest state with subsequent apoptosis induction or in a senescence-like G1 state
during which cell cycle PHASE do the anti-mitotics act?
docetaxel and pacitaxel act during M phase
(mitotic phase)
what is the detailed mechanism of action of anti-mitotic drugs: vincristine/vinblastine?
- these drugs are alkaloid derivatives of plants –> acting as spindle poisons
- Depolymerize MTs –> disrupting cytoskeletal structure
*
- Depolymerize MTs –> disrupting cytoskeletal structure
which anti-mitotics enhance tubulin polymerization?
-
paclitaxel and docetaxel both enhance tubulin polymerization; preventing chromosomes from separating
- “suppression of microtubule dynamics”
- bind specifically to dimeric form of tubulin –> cannot achieve spindle configuration for mitosis –> mitotic arrest at metaphase –> apoptosis
VINBLASTINE:
indications, adverse effects
- indicated for: systemic Hodgkin’s disease
- adverse effects:
- acute: nausea and vomiting
- delayed: marrow suppression and alopecia
VINCRISTINE:
indications, adverse effects
- indication: combination chemo w/ prednisone in acute leukemia in children (pt of CHOP protocol)
- adverse effects:
- **ONLY DELAYED TOXICITY: significant incidence of neurotoxicity
PACLITAXEL:
indications, adverse effects
- indicated for: ovarian CA, advanced breast CA
- adverse effects:
- acute: nausea/ vomiting. hypotension, arrythmias
- delayed: bone marrow suppression,
DOCETAXEL:
indications, adverse effects
- indicated for: breast, prostate, and non-small cell cancers
- adverse effects:
- *DELAYED ONLY: alopecia and hematological effects
which two antimitotics display ONLY DELAYED ADVERSE EFFECTS?
- VINCRISTINE and DOCETAXEL;
- Doc Cristine - delayed
process of a bacterial mutation analysis
- (administering tumor-causing drugs into patient – using SELECTIVE PRESSURE to determining effects)
- tx cells w/ an agent that induces mutations
- grow cells on media which SELECTS FOR these mutations
- only cells w/ that mutation will grow
- subsequently will form colonies (only those that are mutated/resistant would be able to do so)
how is bacterial mutation analysis relevant to cancer therapy?
- many agents induce mutations (esp cell cycle non-specific drugs);
- alkylating agents, antibiotics
- as pt receives therapy –> cancer cells are exposed to mutagens
- mutant cells selected by their ability to grow while tx continues
