alkylating agents and hormonal agents

Question 1

mechanism pf action for alkylating agents

Answer 1

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

Question 2

As a class, alkylating agents cause:

1. ________ as a dose limiting SE.
2. main effect is on _______
3. all agents cause (2)
4. _______ may occur in younger patients being treated with these gents
5. after years of treatment there is a risk of _________

Answer 2

1. myelosupression as a dose limiting SE.
2. main effect is on neutrophils
3. all agents cause nausea and vomiting
4. sterility may occur in younger patients being treated with these gents
5. after years of treatment there is a risk of secondary malignancies such as leukemia

Question 3

forms a reactive electrophile that covalently binds to DNA, forming DNA crosslinks

Answer 3

platinum

Question 4

aquated platinum reacts rapidly with binding sites, preferentially binding to ________

what is the most common binding to least: DNA, proteins, RNA

Answer 4

aquated platinum reacts rapidly with binding sites, preferentially binding to N7 (guanine/adenine)

what is the most common binding to least:RNA> DNA>proteins

Question 5

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?

Answer 5

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.

Question 6

(3) platinum analogues

Answer 6

1/ cisplatin

2. oxaliplatin
3. carboplatin

Question 7

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)

Answer 7

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

Question 8

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.

Answer 8

cisplatin

Question 9

cisplatin nephrotoxicity

1. related to peak ______
2. leads to the inactivation of ___________
3. affects the–> (3)
4. the effects on the kidneys is dose _____
5. 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?
6. chronic phase: stable but there is reduced_____and the _________can be normal or increased
7. can cause anemia due to the

Answer 9

1. related to peak plasma levels
2. leads to the inactivation of renal brush border enzymes
3. affects the–> loop of henle, distal tubules and collecting ducts
4. the effects on the kidneys is dose related
5. 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
6. chronic phase: stable but there is reduced GFR and the serum creatinine can be normal or increased
7. can cause anemia due to the decreased epo production

Question 10

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).

Answer 10

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).

Question 11

oxaliplatin MOA

Answer 11

it will DNA adducts between purine/pyramidine bases leading to inhibiting DNA synthesis and inducing apoptosis

Question 12

Synergistic in vitro with 5-fluorouracil

Answer 12

oxaliplatin

Question 13

oxaliplatin:

1. half life is
2. protein binding > or < to albumin and gamma globulin
3. excretion is primarily through ____
4. toxicities: (4)

Answer 13

1. half life is 391 hr
2. protein binding > 90% to albumin and gamma globulin
3. excretion is primarily through urine
4. toxicities: (4) (1) neurotoxicity triggered by cold (2) myelosuppression (3) hepatotoxicity (4) asthenia

Question 14

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.

Answer 14

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.

Question 15

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.

1. it has a half-life of only ____ hr but the oral bioavailability is ____%. its peak values are 2-3 hr after dose.

Answer 15

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.

1. 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.

Question 16

Cyclophosphamide is metabolized in the _____ to active alkylating species, which are then cleared ____.

Answer 16

liver then leared renally

Question 17

Two major metabolites of cyclophosphamide:

Answer 17

1. phosphoramide mustard (active alkylating species) and

2. acrolein (urotoxic species)

Question 18

can cause urotoxicity in the form of hemorrhagic cystitis.

Answer 18

acrolein

Question 19

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 ________

Answer 19

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.

Question 20

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 __________

Answer 20

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.

Question 21

Ifosfamide metabolism also produces the urotoxic metabolite _______ but in greater/lesser quantity than cyclophosphamide.

Answer 21

Ifosfamide metabolism also produces the urotoxic metabolite acrolein, and in greater quantity than cyclophosphamide.

Question 22

Ifosfamide can cross the ________, thus causing neurotoxicity.

Answer 22

Ifosfamide can cross the blood-brain barrier, thus causing neurotoxicity.

Question 23

Ifosforamide ______ major transport form

Answer 23

Ifosforamide mustard major transport form

Question 24

Ifosfamide has variable pharmacokinetics affected by multiple factors, including the size of the dose, age, body mass index, renal and hepatic function.

Answer 24

yep

Question 25

toxicity of ifosfamide:

1. neutotoxicity manifests as (4)
2. treatment s to stop drug and give
3. renal damage resulting in _______ but ________ is used to prevent it

Answer 25

1. neutotoxicity manifests as lethargy, confusion, seizures and encephalopathy
2. treatment s to stop drug and give methylene blue
3. renal damage resulting in acute tubular necrosis but hydration is used to prevent it

Question 26

Endogenous steroids are derived from

Answer 26

Endogenous steroids are derived from cholesterol.

Question 27

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.

Answer 27

Danazol

Question 28

For treatment of lymphocytic leukemias and lymphomas, ___________ are used for cytolytic action.

Answer 28

glucocorticoids like prednisone

Question 29

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.

Answer 29

lymphocytic

Question 30

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.

Answer 30

anti-androgens like flutamide, bicalutimide and nilutamide

Question 31

________ 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.

Answer 31

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.

Question 32

______ 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.

Answer 32

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.

Question 33

Aromatase inhibitors inhibit the_____ enzymes required for the final steps of ______ production via peripheral aromatization of androgens.

Answer 33

Aromatase inhibitors inhibit the P450 enzymes required for the final steps of estrogen production via peripheral aromatization of androgens.

Question 34

Exemestane is an irreversible steroidal _______inhibitor inhibitor

side effects include:

Answer 34

Exemestane is an irreversible steroidal aromatase inhibitor

side effects include: hot flashes, fatigue and headache

Question 35

Anastrozole and letrozole are both selective and reversible non-steroidal ______ inhibitors

Answer 35

aromatase

Question 36

LH-RH (Luteinizing Hormone Releasing Hormone) agonists work via ________ feedback inhibition of the pituitary, ultimately resulting in _________ production of endogenous testosterone and estrogen.

Answer 36

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.

Question 37

LH-RH agonist (2) and major side effect includes

Answer 37

1. leuprolide
2. 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.