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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
Q

Where is bleomycin hydrase found in the body?

A

Every tissue except skin and lungs

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26
Q

Bleomycin MOA?

A

Binds with iron to take a hydrogen atom from deoxyribose which breaks DNA strands

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27
Q

Bleomycin AE?

A

5-10% will experience pulmonary fibrosis even months after therapy.

> 40yrs and total dose attribute to pulmonary toxicity risk

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28
Q

Topoisomerase I vs II, what kind of DNAs do they work on?

A

I on ssDNA breaks

II on dsDNA breaks

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29
Q

Topoisomerase inhibitors are most toxic in which DNA replication stage?

A

S phase, active replication

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30
Q

What are the topoisomerase I inhibitors?

A

Irinotecan and topotecan

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31
Q

What chemical modifications are done to irinotecan and topotecan?

A

C10 (irine) and C9 (topo) incorporate basic amines for salt formation and solubility

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32
Q

Irinotecan metabolism?

A

Prodrug converted via hepatic carboxyl estereases to SN-38

SN-38 to inactive metabolite via UGT1A1

Asians have polymorphisms with the inactive metabolite

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33
Q

How do you manage irinotecan toxicity?

A

Diarrhea, give loperamide

34
Q

What is required when giving etoposide and teniposide?

A

Those Rx are water INsoluble and required solubility enhancers for IV dosing

35
Q

Etoposide metabolism?

A

CYP3A4, forms catechol, then oxidation forms orthoquinone. Orthoquinone is linked to leukemia in children

36
Q

What causes etoposide leukemia?

A

Chromosomal translocation

37
Q

AE of Anthracycline Topoisoermase II inhibitors?

A

-rubicin (doxorubicin)

Generates free radicals with sometimes irreversible cardiotoxicity

38
Q

Doxorubicin metabolism?

A

Aldoketoreductase reduces C13 to produce secondary alcohol that’s linked to that cardiotoxicity

39
Q

Managing doxorubicin toxicity?

A

Give dexrazoxane (iron chelating drug)

40
Q

Mitoxantrone vs Doxorubicin and cardiotoxicity? Special AE of Mitoxantrone?

A

Mitoxantrone lacks C13 and less cardiotoxic

Causes blue-green feces/urine sometimes in skin and sclera

41
Q

Aresenic Trioxide uses and AE?

A

APL, caused by translocation of chromosomes 15 and 17

Induces remission in APL and apoptosis in malignant cells

42
Q

Hydroxyurea uses?

A

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
Q

Antimetabolite MOA

A

Inhibits synthesis of nucleotides

Targets enzymes

44
Q

Which part of the cell cycle do antimetabolites target?

A

S phase

45
Q

What are the pyrimidine antimetabolites?

A

5-FU

46
Q

What are the purine antimetabolites?

A

Mercaptopurine

47
Q

5-FU metabolism?

A

Capecitabine is the prodrug that is converted to 5-FU

48
Q

What enzyme does 5-FU target?

A

Inhibit thymidylate synthase and w/o dTMP cell will die

Thymidylate synthase is not regenerated if there is no hydrogen

49
Q

5-FU toxicity?

A

Inactivated by DPD in liver, intestines, tumor cells

DPD deficiency in AA and women

50
Q

How do you enhance 5-FU activity?

A

Leucovorin (exogenous folate); can be used with methotrexate toxicity

51
Q

Capecitabine vs 5-FU, which one has more AE?

A

Capecitabine, “hand-foot syndrome” + inhibits CYP2C9

52
Q

Methotrexate PK?

A

Minimal CNS concentrations. High doses with long infusions or intrathecal dosing is required for cytotoxic CNS levels

53
Q

Antifolate MOA?

A

Inhibits DHFR

54
Q

Cytidine class info? (Cytarabine, Gemzar, azacitidine)

A

All have to be biotransformed to their triphosphate derivatives

55
Q

What is the primary mechanism of resistance to cytarabine?

A

Loss of kinase via deoxycytidine kinase

56
Q

Which cytidine rx can be mistakenly incorporated in DNA chain?

A

Cytarabine and Gemzar (inhibits DNA polymerase and blockers further elongation)

57
Q

Cytarabine uses?

A

Lymphomatous meningitis via DepoCyt

Low levels in CNS

58
Q

Urinary elimination product of Gemzar? Issues?

A

dFdU

dFdU Accumulates in renally dysfunctional pt

Should not be used in other radiotherapy drugs

59
Q

Azacitidine MOA?

A

Covalently bound to methyltransferase. Transfers methyl group to DNA

60
Q

What are the purine antimetabolite drugs? What are they used for

A

Mercaptopurine, fludarabine, and cladribine

Flu + cla used for CLL and lymphomas

61
Q

Mercaptopurine metabolism?

A

Converts to ribonucleotide and inhibits AMP + GMP

62
Q

Mercaptopurine MOA?

A

RLS is conversion of PRPP into PRA by ATase

Mercaptopurine inhibits ATase via HGPRT

63
Q

Mercaptopurine toxicity?

A

Poor TPMT metabolizers will get myelosuppression. Take with allopurinol

64
Q

Which process do antimitotic agents disrupt?

A

M phase causing cell cycle arrest via microtubules

65
Q

What do tubules go through during cell division?

A

Polymerization and depolymerization

66
Q

What drugs inhibit and promote assembly of microtubules?

A

Vinca - inhibits

Taxanes + epothilones - promote

67
Q

Vinca resistance?

A

Via MDR1 gene and P-gp

Reduce dose in hepatic dysfunction

68
Q

Half of US kids w/ cancer recieve this chemo…

A

Vincristine

69
Q

Vincristine AE?

A

Peripheral neuropathy

Inj in CSF causes coma and seizures

70
Q

Vinblastine AE?

A

Myelosuppression

No neuro AE

71
Q

Vinorelbine AE?

A

Granulocytopenia

Mild neuro AE

72
Q

Functional group of the taxanes (cabazitaxel, docetaxel, paclitaxel)?

A

Docetaxel and cabazitaxel (C13) enhance chemo potency and C10 of docetaxel enhances solubility vs paclitaxel

73
Q

Taxane MOA?

A

Binds to Beta-tubulin to promote elongation and inhibit depolymerization

74
Q

What contributes to Taxane resistance?

A

Cellular efflux via P-gp

75
Q

Metabolism of Paclitaxel?

A

CYP3C8

76
Q

Metabolism of Cabazitaxel?

A

Demethylation by CYP3A4/5 and forms 3 metabolites included docetaxel

77
Q

Paclitaxel formulation

A

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
Q

Docetaxel formulation

A

Improved solubility vs paclitaxel (uses polysorbate 80). Causes fluid retention

Pre-tx still required

79
Q

Cabazitaxel formulation

A

Also uses polysorbate 80, , but doesnt cause fluid retention

Esters found in rx reduce it to alcohols which improve BBB penetration

80
Q

Epothilone stability vs taxanes

A

Less susceptible to P-gp resistance vs taxanes

Ixabepilone contains lactam which increases stability vs epothilone

81
Q

Ixabepilone formulation

A

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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