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MCC > Wk 3 Chemotherapy > Flashcards

Wk 3 Chemotherapy Flashcards

1
Q

Adjuvant chemotherapy

A

also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness
– Reduce local and distant recurrence after surgery

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2
Q

Neoadjuvant chemotherapy

A

Prior to surgical resection to improve results

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3
Q

Primary Chemotherapy

A

– Palliative in advanced (incurable) disease
– Curative in select diseases (primarily hematologic)
-first chemo

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4
Q

What are 4 types of primary chemotherapy?

A
  1. Induction: treatment of disease to
    achieve remission
  2. Consolidation chemotherapy: given after induction to control microscopic disease
  3. Maintenance chemotherapy: given over long-term basis to maintain remission
  4. Salvage chemotherapy: chemotherapy given after relapse or refractory to previous therapy
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5
Q

What is the gompertzian model?

A

response to chemo depends on position on growth curve
-how many cells are in rapid growth phase

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6
Q

What is the log-kill hypothesis?

A

Curability dependent on if you can give enough cycles of chemotherapy before resistance ensues
-a given chemotherapy is predicted to kill a constant fraction of cells as opposed to a constant number – 1st order kinetics
– Inverse relation between cell number and curability – Race of time to cure versus resistance

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7
Q

What are the 3 phases of chemotherapy?

A
  1. induction
  2. consolidation
  3. maintenance
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8
Q

What is the limit of detection?

A

Determined by scans, BM biopsies, etc, below which cancer cannot be detected

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9
Q

How much kill is the goal after one cycle of chemotherapy in logarithmic theory?

A

~99.9%

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10
Q

BIggest toxicities w/ chemo?

A

-huge decrease in rapidly dividing cells:
-WBC -> infection
-platelets -> bleeding
-RBC -> anemia
-GI tract -> vomiting

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11
Q

What are microtubule chemo agents and what part of the cell cycle do they interupt?

A

Mitotic phase
-taxanes
-Vincas

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12
Q

What are 3 cell cycle non-specific chemotherapies?

A

1.Alkylating agents
2. platinums
3. nitrosoureas

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13
Q

What chemotherapies are antimetabolites and what cell cycle phase do they interupt?

A

S phase:
1. antifolates (methotrexate)
2. antipyrimidines
3. antipurines
4. misc - hydroxyurea, procarbazine

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14
Q

IMP cell cycle chemo target meds

A
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15
Q

Therapeutic index

A
  • Efficacy—maximize cell kill
  • Toxicity—minimize host damage
  • Therapeutic Index is narrow (<10x) for many chemotherapies
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16
Q

What are 4 dosage factors that can be manipulated in chemotherapy?

A
  1. Dose escalation
  2. Reduce the interval: “dose dense”
  3. Sequential scheduling
  4. Combination Chemotherapy - don’t have overlapping toxicities
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17
Q

3 principles of combination chemo

A
  1. Drugs should be effective against the cancer type – Goal of additive or synergistic activity
  2. Each agent should act through a different mechanism
    – Avoid resistance
  3. Drugs with different dose-limiting toxicities should be
    combined
    – Use of full or nearly full therapeutic doses
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18
Q

Cisplatin
MOA
ADE

A
  • MOA: cross-linking DNA
  • ADE: nephrotoxicity, ototoxicity
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19
Q

Etoposide

A
  • MOA: topoisomerase inhibitor
  • ADE: bone marrow suppression
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20
Q

Radiation

A
  • MOA: DNA damage via free radical formation * AE: local burn/irritation
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21
Q

Common combination regime

A

Cisplatin + Etoposide + radiation

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21
Q

Common combination regime

A

Cisplatine + Etoposide + radiation

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22
Q

Timeframe for myelosuppression w/ myeloablation

A
23
Q

Timeframe for myelosuppression w/ mild chemotherapy

A
24
Q

Timeframe for myelosuppression w/ strong chemotherapy

A
  • most pts get sick w/ infection and those infections come from norm bacteria w/in GI tract
25
Q

4 resistant tx failures

A
  1. Pharmacologic
    – Inadequate drug dose – Suboptimal scheduling
  2. Host determinants (physiologic): – Patient general status
    – Immunocompetence
    – Sanctuary sites
    – Poor drug penetration
  3. Primary resistance: absence of initial response to chemotherapy
  4. Acquired resistance: develops in response to anticancer therapy
    – Goldie-Coleman hypothesis predicts tumor cells mutate to a resistant phenotype at a rate dependent on their intrinsic genetic instability
26
Q

7 mechanisms of acquired resistance

A
  1. Expression of drug transport proteins – Efflux: P-glycoprotein / MDR1
    – Influx: OATP, OCT
  2. Altered expression of molecular targets
  3. Intracellular redistribution of drug
  4. Detoxification of drug
  5. Decreased activation
  6. Enhanced DNA repair
  7. Altered apoptotic pathways
27
Q

What are alkylating agents?

A

Exert cytotoxic effects by binding directly to DNA
-nitrogen on guanine is most common target
-not cell cycle specific
-damaged DNA can be repaired, primarily targets rapiding dividing tumors

28
Q

What are 5 alklyating agent subclasses

A
  1. nitrogen mustards
  2. nitrosoureas
  3. triazenes and methylhydrazine
  4. misc
  5. platinums (alkylator-like, less effective)
29
Q

How do alkylators work?

A

They develop crosslinks in DNA
-monoalkylated
-crosslinked (interstrand..bigger effect…ER more serious)
-crosslinked (intrastrand…platinums)

30
Q

Can we gain resistance to alkylators?

A

Yes, via various mechanisms

31
Q

What are 3 alkylating agent toxicities?

A
  1. premature ovarian failure and azoospermia
  2. alopecia
  3. leukemogenic (peaks 5-7 yrs after therapy, similar to myelodysplastic syndrome) - accumulation of DNA damage
32
Q

What kind of drug is cyclophosphamide?
Where is it activated?

A

Nitrogen mustard
-must be activated by CP450 in liver
- -> development of cytotoxic acrolein (which is also bladder toxic)

33
Q

What is acrolein?

A

a substrate of cyclophosphamide that is toxic to the bladder, ruining the bladder wall -> hematuria

34
Q

How are nephrotoxic and urotoxic metabolites from cyclophosphamide managed?

A

Acrolein is the toxic metabolite
-prevented by hydration and coadministration of mesna, which binds to acrolein so it gets peed out w/o damaging the bladder

35
Q

What are 3 platinums?

A
  1. cisplatin
  2. carboplatin
  3. oxaliplatin

-slightly less potent and less toxic

36
Q

What are platinum side effects?

A
  1. nephrotoxicity (cisplatin)
  2. nausea/vomiting
  3. ototoxicity
  4. neurotoxicity (acute -cold-induced distal dysesthesia, cummulative - irreversible sensory peripheral neuropathy)
  5. hypersensitivity
37
Q

What are antimetabolites?

A

Drugs that are structurally similar to naturally occurring compounds (AA, DNA, RNA, etc)
-damage DNA via:
1. competitive enzyme inhibitors
2. incorporating directly into DNA or RNA

All are cell cycle specific: S-phase

38
Q

3 subclasses of antimetabolites

A
  1. Folic acid analogs
  2. Purine analogs
  3. Pyrimidine analogs
39
Q

MOA of methotrexate (MTX)

A

-modified form of folic acid, which is necessary for synthesis of purine nucleotides
-folic acid converted to active form by DHFR
-MTX binds to DHFR as a competitive inhibitor, prevents folic acid’s contribution to DNA synthesis by blocking conversion of FH2 to FH4

40
Q

When is Methotrexate used?

A

-anything in brain b/c it has good penetration into CSF
-IV, PO, IM, Intra-thecal (IT)
-active transport into cells, actively secreted in proximal tube for renal excretion (~80%)
-hydration is key
-alkalinization is key to prevent MTX precipitation in renal tubule and prevent nephrotoxicity
-use leucovorin 12-24 hrs after end MTX (high exposure 24-36 hrs)
-antidote = glucarpidase - enzymatically inactivates MTX & VERY expensive
-monitor serum concentrations until clear

41
Q

What is leucovorin?

A

Activated folic acid
-administered 12-24 hrs after high does MTX
-directly converted to THFR 4 for purine and pyrimidine synthesis bypassing MTX inhibition
-used to rescue BM and GI mucosal cells

42
Q

MTX toxicity

A

Dependent on exposure duration:
-myelosupporession
-mucositis
-hepatotoxicity
nephrotoxicity

43
Q

What kind of drug is fluorouracil?

A

A pyrimidine analog, mimics uracil
-5-FU
-gets incorporated into RNA, impairs RNA/DNA
-suicide inhibitor of thymidylate synthase (converst 5,10 methylene THF to dihydrofolate)

44
Q

5-FU delivery methods and associated toxicities

A
  1. Continuous infusion -> hand-foot syndrome (palmar-plantar erythrodysethesia)
  2. Bolus -> myelosuppression (BM)

Other side effects: mucositis, stomatitis, diarrhea, N/V
If pt has dihydropyrimidine dehydrogenase (DPD) deficiency (~8% population) -> increased toxicity

Antidote = uridine triacetate

45
Q

How is leucovorin used w/ 5-FU?

A

MOA: folinic acid -> enhanced FdUMP inhibition of thymidylate synthase
-also for MTX rescue

46
Q

What is capecitabine?

A

Oral prodrug of 5-FU
-0 to 80% bioavailability
-Toxicity:
1. hand-foot syndrome
2. mucositis (less than bolus 5-FU)
3. myelosuppression (“)
4. diarrhea

47
Q

Management of hand-foot syndrome

A
  1. Skin care - wash w/ cool water, use moisturizers/keratolytic
  2. avoid tight clothes (belts, bras, shoes)
  3. avoid activities that cause sweating/abrasions
48
Q

What kind of drug is cytidine?

A

Pyrimidine/nucleoside analog
-can be incorporated into DNA

49
Q

What is cytarabine?

A

A cytidine analog
-has good CNS penetration across BBB
-IV, SQ, or IT
-elimination: urine (inactive metabolites)
-> myelosuppression, neurotoxicity (cerebellar: ataxia), ocular, skin rash, PE, N/V/D/mucositis

50
Q

What are purine analogs?

A

-either look like adenine or guanine
-damage DNA

51
Q

What are ABC transporters?

A

ATP binding cassettes on the membrane like MDR1 (multidrug resistance 1) that use ATP to pump toxins (or drugs) out of cells
-a way that cells become resistant to chemotherapeutic agents

52
Q

T cell markers

A

CD3
CD5

<10 usually T cells

53
Q

B-cell associated markers

A

CD19
CD20 - target of rituximab

54
Q

Stem-cell and progenitor cell-assocated

A

CD34 = immature/precursor leukemia and lymphoma

55
Q

What is TdT used for?

A

To ID stem cell and progenitor cell
-specialized DNA polymerase expressed in immature, pre-B, pre-T lymphoid cells, and acute lymphoblastic leukemia/lymphoma cells

56
Q

What CD marker do B cells show w/ lymphomas?

A

CD5

MCC (44 decks)

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