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
why is it important to knock out ALL mutated cells whil administering chemo?
if not, that ONE resistant cell will amplify over the subsequent treatment cycles
- so if you knock out all but one –> then it will continue to proliferate;
- YOU NEED TO HAVE A MECHANISM to knock out the resistant cell (using combination chemo)**
when genes amplify, what occurs?
- increase in GENE COPY NUMBER
- increase in GENE PRODUCT
Clinical dose is RENDERED INEFFECTIVE (bc there’s so much of the gene, and can’t inc the dose enough)
what alterations in protein structure occurs when a cell becomes resistant to cancer chemo?
- classical mechanism: change in gene structure w/o amplification
-
gene product displays different protein characteristics
- mutation analysis; if pt has cancer –> this can be lethal for the patient
how does a cancer cell become resistant with decreased enzyme activity (mechanisms)?
- decreased gene expression of proteins required for drug metabolism
- active analogues not synthesized (administered as prodrugs)
mechanism of P-glycoprotein alteration (aka multi-drug resistance protein) becoming resistant to cancer chemo
(and examples)
- P-glycoprotein involved in membrane transport
- change in p-glycoprotein alters drug transport into cell or increases its removal from tumor cell
examples:
- methotrexate: decreased uptake
- vinca alklaloids: decreased uptake
what is the purpose of combination chemotherapy, and
how does it work?
- if multiple drugs administered together; will be sure to kill all cells (even if they’re resistant to a certain drug)
DNA repair: functions
- In normal cells, DNA repair functions to maintain the integrity of cellular genetic
information (allows it to go back) - In tumor cells, identical pathways reduce drug efficacy by removal of DNA lesions
formed during therapy - Applies to both chemotherapy and radiation therapy
DNA repair and cancer chemotherapy?
- DNA can be an impediment to effective therapy
- laboratories studied the effects of radiation –> discovered DNA repair pathways
which damaging agents can be corrected by DNA repair pathways?
- strand breaks
- intercalation
- free radical formation
- alkylation
which drug is used for gliomas?
mechanism?
-
Temozolomide (Temodar)
- Alkylating agent used to tx glioma (brain cells have DNA repair pathways too)
- mech: inducses DNA lesions
-
DNA repair:
- temodar induced lesions removed by the DNA repair enzyne, O6-alkylguanine alkyltransferase
