alkylating agents and hormonal agents Flashcards
mechanism pf action for alkylating agents
addition of alkyl groups to electronegative groups on DNA with the formation of reactive intermediates causing inter- intra- strand DNA cross-linking, DNA mispairing ad DNA strand breakage leading to inhibition of DNA replication and cytotoxicity
As a class, alkylating agents cause:
- ________ as a dose limiting SE.
- main effect is on _______
- all agents cause (2)
- _______ may occur in younger patients being treated with these gents
- after years of treatment there is a risk of _________
- myelosupression as a dose limiting SE.
- main effect is on neutrophils
- all agents cause nausea and vomiting
- sterility may occur in younger patients being treated with these gents
- after years of treatment there is a risk of secondary malignancies such as leukemia
forms a reactive electrophile that covalently binds to DNA, forming DNA crosslinks
platinum
aquated platinum reacts rapidly with binding sites, preferentially binding to ________
what is the most common binding to least: DNA, proteins, RNA
aquated platinum reacts rapidly with binding sites, preferentially binding to N7 (guanine/adenine)
what is the most common binding to least:RNA> DNA>proteins
Resistance may be mediated through multiple mechanisms: (1) altered cellular transport leading to __________ drug accumulation within cell, (2) ________ inactivation by thiol-containing compounds, (3) __________ DNA repair activity (ERCC gene), or (4) deficiency in __________ (hMHL1, hMSH2).
Are there currently drugs to reverse resistance?
Resistance may be mediated through multiple mechanisms:
(1) altered cellular transport leading to decreased drug accumulation within cell,
(2) increased inactivation by thiol-containing compounds,
(3) increased DNA repair activity (ERCC gene), or
(4) deficiency in mismatch repair enzymes (hMHL1, hMSH2).
There are currently no drugs to reverse resistance.
(3) platinum analogues
1/ cisplatin
- oxaliplatin
- carboplatin
Cisplatin is highly __________, associated with both acute and delayed nausea and vomiting.
Patients require standing (scheduled dosing) ____
common medications to give: (acute) (3) (delayed) (3)
Cisplatin is highly emetogenic, associated with both acute and delayed nausea and vomiting. Patients require standing (scheduled dosing) anti-emetics for at least 2-3 days after cisplatin dose.
common medications to give: (acute) 5HT antagonist + dexamethasone + nk-1 antagonist (delayed) dexamethasone + dopamine antagonist + lorazepam
Multiple factors increase the risk for acute renal failure with ________, including high peak plasma concentrations, previous cisplatin chemotherapy, underlying kidney damage, hypoalbuminemia, older age, female gender, and concurrent nephrotoxic drugs.
cisplatin
cisplatin nephrotoxicity
- related to peak ______
- leads to the inactivation of ___________
- affects the–> (3)
- the effects on the kidneys is dose _____
- acute phase: Acute renal damage manifests as increased serum creatinine, increased blood urea nitrogen, and decreased glomerular filtration rate and can be progressive with continued cycles with reversible/reversible?
- chronic phase: stable but there is reduced_____and the _________can be normal or increased
- can cause anemia due to the
- related to peak plasma levels
- leads to the inactivation of renal brush border enzymes
- affects the–> loop of henle, distal tubules and collecting ducts
- the effects on the kidneys is dose related
- acute phase: Acute renal damage manifests as increased serum creatinine, increased blood urea nitrogen, and decreased glomerular filtration rate and can be progressive with continued cycles but can be reversed after discontinuation of the drug
- chronic phase: stable but there is reduced GFR and the serum creatinine can be normal or increased
- can cause anemia due to the decreased epo production
Cisplatin is also associated with neurotoxicity, which is ________.
This includes________ (damage to sensory nerves), _________(stocking-glove distribution, associated with a cumulative dose greater than 300 mg/m2), _________ (high frequency loss related to total dose and peak concentration), and ________(not as common).
Cisplatin is also associated with neurotoxicity, which is not reversible. This includes axonal degeneration (damage to sensory nerves), peripheral neuropathies (stocking-glove distribution, associated with a cumulative dose greater than 300 mg/m2), auditory impairment (high frequency loss related to total dose and peak concentration), and visual disturbances (not as common).
oxaliplatin MOA
it will DNA adducts between purine/pyramidine bases leading to inhibiting DNA synthesis and inducing apoptosis
Synergistic in vitro with 5-fluorouracil
oxaliplatin
oxaliplatin:
- half life is
- protein binding > or < to albumin and gamma globulin
- excretion is primarily through ____
- toxicities: (4)
- half life is 391 hr
- protein binding > 90% to albumin and gamma globulin
- excretion is primarily through urine
- toxicities: (4) (1) neurotoxicity triggered by cold (2) myelosuppression (3) hepatotoxicity (4) asthenia
Carboplatin causes _________ rather than nephrotoxicity.
When given in combination with a _____ (ie paclitaxel) sequence of drug administration is critical to avoid toxicity –it should be given before or after to platinum.
Carboplatin causes neurotoxicity rather than nephrotoxicity. When given in combination with a taxane (ie paclitaxel) sequence of drug administration is critical to avoid toxicity – taxane should be given first followed by platinum.
Cyclophosphamide falls in the sub-class of __________, and is a pro-drug that needs to be metabolized to an active alkylating form. The mechanism of action is similar to other alkylators.
- it has a half-life of only ____ hr but the oral bioavailability is ____%. its peak values are 2-3 hr after dose.
Cyclophosphamide falls in the sub-class of nitrogen mustards, and is a pro-drug that needs to be metabolized to an active alkylating form. The mechanism of action is similar to other alkylators.
- it has a half-life of only 3-10 hr but the oral bioavailability is 97%. its peak values are 2-3 hr after dose.
Cyclophosphamide is metabolized in the _____ to active alkylating species, which are then cleared ____.
liver then leared renally
Two major metabolites of cyclophosphamide:
- phosphoramide mustard (active alkylating species) and
2. acrolein (urotoxic species)
can cause urotoxicity in the form of hemorrhagic cystitis.
acrolein
Major toxicities of cyclophosphamide also include acute and delayed nausea/vomiting, requiring patients to have scheduled anti-emetics after dosing.
Cyclophosphamide can cause neutropenia and lymphopenia, and is thus both ________ and _________. Due to the ____________effect it is also used in rheumatologic and auto-immune diseases.
High doses (used in stem cell transplants) can lead to irreversible ________
Major toxicities of cyclophosphamide also include acute and delayed nausea/vomiting, requiring patients to have scheduled anti-emetics after dosing.
Cyclophosphamide can cause neutropenia and lymphopenia, and is thus both myelosuppressive and immunosuppressive.
Due to the immunosuppressive effect it is also used in rheumatologic and auto-immune diseases.
High doses (used in stem cell transplants) can lead to irreversible cardiac necrosis.
Ifosfamide is structurally similar to cyclophosphamide, and is also a pro-drug, requiring activation by _____ enzymes. Metabolism of ifosfamide takes longer than cyclophosphamide, leading to a __________
Ifosfamide is structurally similar to cyclophosphamide, and is also a pro-drug, requiring activation by liver enzymes. Metabolism of ifosfamide takes longer than cyclophosphamide, leading to a longer half-life.
Ifosfamide metabolism also produces the urotoxic metabolite _______ but in greater/lesser quantity than cyclophosphamide.
Ifosfamide metabolism also produces the urotoxic metabolite acrolein, and in greater quantity than cyclophosphamide.
Ifosfamide can cross the ________, thus causing neurotoxicity.
Ifosfamide can cross the blood-brain barrier, thus causing neurotoxicity.
Ifosforamide ______ major transport form
Ifosforamide mustard major transport form
Ifosfamide has variable pharmacokinetics affected by multiple factors, including the size of the dose, age, body mass index, renal and hepatic function.
yep
toxicity of ifosfamide:
- neutotoxicity manifests as (4)
- treatment s to stop drug and give
- renal damage resulting in _______ but ________ is used to prevent it
- neutotoxicity manifests as lethargy, confusion, seizures and encephalopathy
- treatment s to stop drug and give methylene blue
- renal damage resulting in acute tubular necrosis but hydration is used to prevent it
Endogenous steroids are derived from
Endogenous steroids are derived from cholesterol.
is a synthetic derivative of ethinyl testosterone and in oncology is used mainly as a second-line agent in the treatment of bone marrow failure syndromes and myelodysplasia.
It can suppress pituitary output of FSH and LH.
Side effects include edema, flushing, hypertension, hirsutism, voice changes (hoarseness, changing pitch), and increases in leukocytes, erythrocytes, and/or platelets.
Danazol
For treatment of lymphocytic leukemias and lymphomas, ___________ are used for cytolytic action.
glucocorticoids like prednisone
Glucocorticoids are also used for immunosuppressive effects, reducing activity and number of __________ cells.
Major side effects of short term use include glucose intolerance, insomnia, agitation, appetite stimulation and weight gain, and fluid retention.
lymphocytic
bind androgen receptor and inhibits uptake and binding in nucleus
Most common side effects include hot flashes, gynecomastia and breast tenderness, impotence, and decreased libido, and transient LFT abnormalities.
anti-androgens like flutamide, bicalutimide and nilutamide
________ compete with endogenous estrogen to bind estrogen receptors, and have both partial agonist and antagonist actions at the receptor.
Agents are cell cycle-specific, working in _____phase. They also stimulate TGF-beta, which inhibits TGF- alpha and IGF-1, leading to ____________.
Anti-estrogen agents are used to treat breast cancer.
Anti-estrogens compete with endogenous estrogen to bind estrogen receptors, and have both partial agonist and antagonist actions at the receptor.
Agents are cell cycle-specific, working in G1 phase. They also stimulate TGF-beta, which inhibits TGF- alpha and IGF-1, leading to decreased proliferation of the cell.
Anti-estrogen agents are used to treat breast cancer.
______ is the main anti-estrogen in use, extensively utilized to treat breast cancer, and has both anti-estrogen and pro-estrogen effects depending on tissue binding. It competitively binds estrogen receptors in tumors and normal tissues. In breast and vaginal tissue, it has anti-estrogenic actions, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. In bone, endometrium, and lipids, it has pro-estrogenic activity.
Tamoxifen is the main anti-estrogen in use, extensively utilized to treat breast cancer, and has both anti-estrogen and pro-estrogen effects depending on tissue binding. Tamoxifen competitively binds estrogen receptors in tumors and normal tissues. In breast and vaginal tissue, tamoxifen has anti-estrogenic actions, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. In bone, endometrium, and lipids, tamoxifen has pro-estrogenic activity.
Aromatase inhibitors inhibit the_____ enzymes required for the final steps of ______ production via peripheral aromatization of androgens.
Aromatase inhibitors inhibit the P450 enzymes required for the final steps of estrogen production via peripheral aromatization of androgens.
Exemestane is an irreversible steroidal _______inhibitor inhibitor
side effects include:
Exemestane is an irreversible steroidal aromatase inhibitor
side effects include: hot flashes, fatigue and headache
Anastrozole and letrozole are both selective and reversible non-steroidal ______ inhibitors
aromatase
LH-RH (Luteinizing Hormone Releasing Hormone) agonists work via ________ feedback inhibition of the pituitary, ultimately resulting in _________ production of endogenous testosterone and estrogen.
LH-RH (Luteinizing Hormone Releasing Hormone) agonists work via negative feedback inhibition of the pituitary, ultimately resulting in decreased production of endogenous testosterone and estrogen.
LH-RH agonist (2) and major side effect includes
- leuprolide
- goserelin
Major SE is a tumor flare due to an initial release of LH and FSH. This results in initial short-term disease flare with symptoms of increased pain and flushing for the first week or two of therapy.
