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IPT: Hem/Onc/Transplant > Block 1 > Flashcards

Block 1 Flashcards

1
Q

What is senescence and apoptosis?

A

Senescence — The phenomena by which normal cells cease to divide and are refractory to growth factor stimulation

Apoptosis — A programmed destruction of cells that keeps cell numbers in check by eliminating senescent cells or those without useful function

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2
Q

In general, which kind of cells are most vulnerable to cytotoxic action of anticancer agents?

A

Cancer cells

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3
Q

Which atoms of guanine are susceptible to formation of a covalent bond with alkylating agents?

A

N7 and O6

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4
Q

What is the bis (Beta-chlorethyl) group?

A

Cl-C-C-S-C-C-Cl (sulfur mustard)

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5
Q

What effect does nitrogen mustard have on DNA molecules?

A

Interstranding cross-links which damages them (N7 alkylates them on guanine by forming aziridinium ions)

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6
Q

Difference of aziridinium ion formation via alkyl and aryl nitrogen mustard?

A

Alkyl one has a methyl group (e- donating) forms the ion quickly. Theres a lack of specificity with increases AE and dose-limiting toxicity

Aryl has a benzene group (e- withdrawing) with forms the ion slowly with sufficientlyq controlled reactivity to attenuate AE

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7
Q

Chlorambucil and Melphalan dosages?

A

Chlorambucil - oral good, food decreases absorption

Melphalan - oral available, but erratic absorption, also IV

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8
Q

Bendamustine dosage and important info?

A

30 min IV infusion

DNA damage is more extensive vs other nitrogen mustard

AE of hypersensitivity/anaphylaxis, give antihistamines and corticosteroids prior

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9
Q

What is the most used nitrogen mustard? MOA?

A

Cyclophosphamide

Needs metabolic activation for alkylation and hepatic metabolism contributes to kidney/bladder toxicity

but….less effect on peripheral blood PLT ct and less mucosal damage vs other alkylating agents

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10
Q

Cyclophosphamide and their metabolites? Damages?

A

Produces Chloracetaldehyde and Acrolein

Chloroacetaldehyde is nephrotoxic and neurotoxic

Acrolein damages kidney and bladder

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11
Q

What is the most neurotoxic DNA alkylating agent? Their metabolites?

A

Ifosfamide

Also produces Chloracetaldehyde and Acrolein, but mainly Chloracetaldehyde

Give adequate hydration to reduce bladder toxicity

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12
Q

What is given to manage toxicity of ifosfamide and high dose cyclophosphamide?

A

Mesna; makes Acrolein more water soluble

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13
Q

Busulfan MOA and issues?

A

1+ methylsulfonate ester can be displaced via N7 of guanine

Severe pancytopenia, recovery can take up to 2 yrs

Pulmonary toxicity at high dose

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14
Q

Nitrosoureas MOA and repair?

A

Alkylates O6 of guanine to cross-link DNA

Repaired by MGMT which can reverse the first alkylation

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15
Q

What are the nitrosoureas?

A

Carmustine and Lomustine

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16
Q

Uses of nitrosoureas and damages?

A

Highly lipophilic (crosses BBB) to treat brain tumors.

Causes CNS toxicity

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17
Q

Triazene MOA?

A

Also focuses on O6 like nitrosoureas.

But instead the drugs generate MTIC which METHYLATE DNA

Also has MGMT

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18
Q

Special AE of Temozolomide?

A

Women clear it less effectively so they have higher incidence of neutropenia and thrombocytopenia

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19
Q

How do platinum agents affect DNA?

A

INTRAstranding, not interstranding like the mustards

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20
Q

Platinum agent MOA?

A

Enters cells by active copper transporter CTR1

Chloride is displaced and replaced by water

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21
Q

Cisplatin PK and damage?

A

Reacts with aluminum and must be protected from light

Removed via kidneys but causes a lot of damage to renal tubules

Hydrate with chloride containing solutions

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22
Q

How do you manage cisplatin toxicity?

A

Tx with amifostine primarily for renal toxicity not so much for ototoxicity

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23
Q

Carboplatin vs Cisplatin, intermediate formation?

A

Carboplatin just forms intermediates slower

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24
Q

What is the mechanism of resistance for platinum agents?

A

MMR; less likely to be seen in oxaliplatin because it is less dependent on CTR1

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25
Where is bleomycin hydrase found in the body?
Every tissue except skin and lungs
26
Bleomycin MOA?
Binds with iron to take a hydrogen atom from deoxyribose which breaks DNA strands
27
Bleomycin AE?
5-10% will experience pulmonary fibrosis even months after therapy. >40yrs and total dose attribute to pulmonary toxicity risk
28
Topoisomerase I vs II, what kind of DNAs do they work on?
I on ssDNA breaks II on dsDNA breaks
29
Topoisomerase inhibitors are most toxic in which DNA replication stage?
S phase, active replication
30
What are the topoisomerase I inhibitors?
Irinotecan and topotecan
31
What chemical modifications are done to irinotecan and topotecan?
C10 (irine) and C9 (topo) incorporate basic amines for salt formation and solubility
32
Irinotecan metabolism?
Prodrug converted via hepatic carboxyl estereases to SN-38 SN-38 to inactive metabolite via UGT1A1 Asians have polymorphisms with the inactive metabolite
33
How do you manage irinotecan toxicity?
Diarrhea, give loperamide
34
What is required when giving etoposide and teniposide?
Those Rx are water INsoluble and required solubility enhancers for IV dosing
35
Etoposide metabolism?
CYP3A4, forms catechol, then oxidation forms orthoquinone. Orthoquinone is linked to leukemia in children
36
What causes etoposide leukemia?
Chromosomal translocation
37
AE of Anthracycline Topoisoermase II inhibitors?
-rubicin (doxorubicin) Generates free radicals with sometimes irreversible cardiotoxicity
38
Doxorubicin metabolism?
Aldoketoreductase reduces C13 to produce secondary alcohol that's linked to that cardiotoxicity
39
Managing doxorubicin toxicity?
Give dexrazoxane (iron chelating drug)
40
Mitoxantrone vs Doxorubicin and cardiotoxicity? Special AE of Mitoxantrone?
Mitoxantrone lacks C13 and less cardiotoxic Causes blue-green feces/urine sometimes in skin and sclera
41
Aresenic Trioxide uses and AE?
APL, caused by translocation of chromosomes 15 and 17 Induces remission in APL and apoptosis in malignant cells
42
Hydroxyurea uses?
Blocks ribonucleotide reductase the rate-limiting step of DNA biosynthesis Causes cell-cycle arrest at G1-S; hydroxyurea is used as a radiation sensitizer
43
Antimetabolite MOA
Inhibits synthesis of nucleotides Targets enzymes
44
Which part of the cell cycle do antimetabolites target?
S phase
45
What are the pyrimidine antimetabolites?
5-FU
46
What are the purine antimetabolites?
Mercaptopurine
47
5-FU metabolism?
Capecitabine is the prodrug that is converted to 5-FU
48
What enzyme does 5-FU target?
Inhibit thymidylate synthase and w/o dTMP cell will die Thymidylate synthase is not regenerated if there is no hydrogen
49
5-FU toxicity?
Inactivated by DPD in liver, intestines, tumor cells DPD deficiency in AA and women
50
How do you enhance 5-FU activity?
Leucovorin (exogenous folate); can be used with methotrexate toxicity
51
Capecitabine vs 5-FU, which one has more AE?
Capecitabine, "hand-foot syndrome" + inhibits CYP2C9
52
Methotrexate PK?
Minimal CNS concentrations. High doses with long infusions or intrathecal dosing is required for cytotoxic CNS levels
53
Antifolate MOA?
Inhibits DHFR
54
Cytidine class info? (Cytarabine, Gemzar, azacitidine)
All have to be biotransformed to their triphosphate derivatives
55
What is the primary mechanism of resistance to cytarabine?
Loss of kinase via deoxycytidine kinase
56
Which cytidine rx can be mistakenly incorporated in DNA chain?
Cytarabine and Gemzar (inhibits DNA polymerase and blockers further elongation)
57
Cytarabine uses?
Lymphomatous meningitis via DepoCyt Low levels in CNS
58
Urinary elimination product of Gemzar? Issues?
dFdU dFdU Accumulates in renally dysfunctional pt Should not be used in other radiotherapy drugs
59
Azacitidine MOA?
Covalently bound to methyltransferase. Transfers methyl group to DNA
60
What are the purine antimetabolite drugs? What are they used for
Mercaptopurine, fludarabine, and cladribine Flu + cla used for CLL and lymphomas
61
Mercaptopurine metabolism?
Converts to ribonucleotide and inhibits AMP + GMP
62
Mercaptopurine MOA?
RLS is conversion of PRPP into PRA by ATase Mercaptopurine inhibits ATase via HGPRT
63
Mercaptopurine toxicity?
Poor TPMT metabolizers will get myelosuppression. Take with allopurinol
64
Which process do antimitotic agents disrupt?
M phase causing cell cycle arrest via microtubules
65
What do tubules go through during cell division?
Polymerization and depolymerization
66
What drugs inhibit and promote assembly of microtubules?
Vinca - inhibits Taxanes + epothilones - promote
67
Vinca resistance?
Via MDR1 gene and P-gp Reduce dose in hepatic dysfunction
68
Half of US kids w/ cancer recieve this chemo...
Vincristine
69
Vincristine AE?
Peripheral neuropathy Inj in CSF causes coma and seizures
70
Vinblastine AE?
Myelosuppression No neuro AE
71
Vinorelbine AE?
Granulocytopenia Mild neuro AE
72
Functional group of the taxanes (cabazitaxel, docetaxel, paclitaxel)?
Docetaxel and cabazitaxel (C13) enhance chemo potency and C10 of docetaxel enhances solubility vs paclitaxel
73
Taxane MOA?
Binds to Beta-tubulin to promote elongation and inhibit depolymerization
74
What contributes to Taxane resistance?
Cellular efflux via P-gp
75
Metabolism of Paclitaxel?
CYP3C8
76
Metabolism of Cabazitaxel?
Demethylation by CYP3A4/5 and forms 3 metabolites included docetaxel
77
Paclitaxel formulation
Limited water solubility, administered in 50% ethanol and 50% castor oil which causes hypersensitivity issues Albumin-bound formulation doesnt need pre-tx Dont mix with drug using CYP2C8
78
Docetaxel formulation
Improved solubility vs paclitaxel (uses polysorbate 80). Causes fluid retention Pre-tx still required
79
Cabazitaxel formulation
Also uses polysorbate 80, , but doesnt cause fluid retention Esters found in rx reduce it to alcohols which improve BBB penetration
80
Epothilone stability vs taxanes
Less susceptible to P-gp resistance vs taxanes Ixabepilone contains lactam which increases stability vs epothilone
81
Ixabepilone formulation
Also has limited water solubility like paclitaxel using 50% castor oil which causes hypersensitivity rxns

IPT: Hem/Onc/Transplant (7 decks)

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