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MOD 3 > Cancer Chemo Principles > Flashcards

Cancer Chemo Principles Flashcards

1
Q

Cancer chemotherapeutic agents kill by what order kinetics? Describe what this is

A

Kills by First Order Kinetics

  • a given dose kills a constant percentage of cells, NOT a constant number
  • if an agent kills 99.9% of tumor volume
    • 106 –> 10 <span>3</span>
    • 103–> 100
    • this means that the same dose which decreases the tumor burden from ^6 to ^3 will be needed to decrease the burden from ^3 to ^0
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2
Q

Definition of growth fraction. What are the implications of it?

A

Growth fraction:

  • proportion of cancer cells that are actively proliferating/dividing at a given point of time
  • represents dividing cells sensitive to chemotherapy
  • a higher growth fraction causes more cancer cells to be killed when they are exposed to specific drug
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3
Q

Definition of mass doubling time

A

Mass doubling time:

  • time required for a mass to double its volume
  • 1/growth fraction
  • dependent on the number of dividing cells
  • inversely proportional to growth fraction, so tumors with shorter mass doubling times = more amendable to chemo
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4
Q

Gompertzian Growth Curve

A

Over time, the growth fraction of the tumors **decreases **such that the peak growth rate occurs before the tumor is detectable

growth fraction is only about 1-4% when tumor is detectable

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5
Q

What is the rationale for debulking and adjunct chemotherapy?

A

debulking= surgical removal of part of malignant tumor which cannot be completely excised, to help enhance effectiveness of chemo

This is done due to concept of Gompertzien growth curve: over time, growth fraction of the tumors decreases. That way, in doing surgery first, there are smaller cells left that are more likely to be proliferating and growing more, thus more responsive to chemo

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6
Q

Mechanism of action of methotrexate

A

Methotrexate is an antimetabolite:

Folic acid analog: inhibits dihydrofolate reductase –> decreases dTMP –> decreases DNA and protein synthesis

recall DHF reductase converts dihydrofolate to tetrahydrofolate

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7
Q

Major side effect of methotrexate

A
  • myelosuppression, which is reversible with leuocovorin (folonic aid)
  • bone marrow
  • hepatic
  • nephrotoxicity
  • **stomatitis **(inflammation of mouth and lips)
  • gastrointestinal
  • macrovesicular fatty change in liver
  • mucositis
  • teratogenic
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8
Q

Major side effects of Cisplatin/Carboplatin (alkylating agent)

A
  • nephrotoxicity
  • hypomagnesemia (goes together with hypocalcemia and hypokalemia, get decrease in PTH release)
  • ototoxicity
  • neurotoxicity (stocking and glove sensorimotor neuropathy)
  • intensely emetogenic (vomiting inducing)
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9
Q

Major side effects of Vincristine/Vinblastine (antimitotic agents)

A
  • peripheral and autonomic neuropathy
  • vinblastine myelosuppression
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10
Q

Major side effects of Daunorubicin/Doxorubicin (antitumor antibiotics, anthracyclines)

A
  • myelosuppression
  • cardiomyopathy
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11
Q

Major side effects of Bleomycin (antitumor antibiotic)

A
  • pulmonary toxicity, may progress to pulmonary fibrosis
  • little myelosuppression
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12
Q

What type of malignancies are hormonal therapies used for?

A

Hormonally regulated organs. Used in breast, prostate, ovarian, and uterine malignancies

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13
Q

In breast cancer, list the main drug that is a selective estrogen receptor modulator

A

Tamoxifen

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14
Q

In breast cancer, list the 2 main aromatase inhibitors. What step is this and where does it occur?

A
  • Exemestane, Anastrazole
  • occur outside the nucleus: aromatase convert androstenedione and testosterone into oestrone and cestradiol before entering the nucleus and binding to estrogen receptors.
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15
Q

List the 3 main types of targeted therapies for prostate cancer

A
  • LHRH analog (leuprolide)
  • Androgen receptor inhibitors (bicalutamide, enzalutamide)
  • 17-a hydroxylase/C17,20 lyase inhibitor (abiraterone)
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16
Q

Hormone therapy toxicities:

Tamoxifen (breast) (7)

A

blood clots, stroke, uterine cancer, cataracts, hot flashes, joint pain, leg cramps

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17
Q

Hormone therapy toxicities:

Exemestane (breast) (3)

Anastrazole (4)

A

Exemestane: hot flashes, arthralgies, osteoporosis

Anastrazole: hot flashes, arthralgies, fractures, cataracts

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18
Q

Hormone therapy toxicities:

Leuprolide (prostate) (5)

A

-hot flashes, impotence, weakness, cardiovascular disease, osteoporosis (LHRH analog, lowering their testoering levels so low)

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19
Q

Hormone therapy toxicities:

Bicalutamide (prostate) (5)

A

-hot flashes, weakness, liver failure, arthralgias, edema

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20
Q

Hormone therapy toxicities:

Abiraterone (prostate) (4)

A

-arthralgies, edema, diarrhea, hypokalemia

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21
Q

4 main types of immunotherapy

A
  • monoclonal antibodies
  • vaccines
  • immunomodulatory drugs
  • checkpoint blockade
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22
Q

two main types of immunomodulatory drugs

A
  • IL-2/interferon
  • thalidomide and derivatives
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23
Q

suffixes for the following:

  • human
  • murine
  • chimeric
  • humanized
A
  • human: umab
  • murine: momab
  • chimeric: ximab
  • humanized: zumab

the more humanized, the less likely you’re going to see a big reaction when we infuse them

24
Q

mechanism of action of monoclonal antibodies

A
  • prevent cell proliferation
    • antibody-dependent cell mediated cytotoxicity (ADCC)
    • complement-dependent cytotoxicity (CDC)
25
Q

Rituximab:

  • target
  • disease
  • side effects
A
  • target: CD-20 (B-cells)
  • disease: CD-20+ lymphoma
  • side effects: infusion reactions, B-cell depletion

(premedicate with steroids, benedryl, H2 blockers)

26
Q

Bevacizumab

  • target
  • disease
  • side effects
A
  • target: VEGF (Vascular endothelial growth factor)
  • disease: colorectal, non-small cell lung, renal
  • side effects: impaired wound healing, thrombosis, HTN, proteinuria
27
Q

Trastuzumab

  • target
  • disease
  • side effects
A
  • target: HER-2/neu (human epidural growth factor) receptor
  • disease: breast, gastric
  • side effects: infusion reactions, cardiac (significant cardiomyopathy, HER-2 is normally express in cardiac tissue)
28
Q

Cetuximab:

  • target
  • disease
  • side effects
A
  • target: EGF receptor
  • disease: colorectal, head and neck, pancreas, non-small cell lung
  • side effects: rash, fatigue
29
Q

Reason for cetuximab rash

A

epidermal growth factor, targeting the skin.

Rashes have the highest response rates, so rash is a good sign

30
Q

Ipilimumab

  • target
  • disease
  • side effects
A
  • target: CTLA-4 (cytotoxic T-lymphocyte antigen-4)
  • disease: metastatic melanoma
  • side effects: colitis, dermatitis, hepatitis, neuropathy

CTLA4 are “brakes” on the immune system. The body has to appropriately shut itself off. Antibody blocks this so it cant shut itself off.

31
Q

Pembrolizumab

  • target
  • disease
  • side effects
A
  • target: PD-1 (programmed death receptor-1)
  • disease: metastatic melanoma
  • side effects: pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyper or hypothyroidism

PD-1 acts as an invisibility cloak to the cancer cells. Cancer cells express these receptors, and they blanket the cancer so the immune system no longer see it. Antibodies target these receptors to this cloak

32
Q

Prostate Cancer Vaccine

  • name
  • how it works/ what it targets
  • side effects
A

Sipuleucel-T

  • WBCs are drawn from pt, locate certain immune system cells
  • cells are exposed to protein found in prostate cancer cells: prostatic acid phosphatase (PAP)
  • alert the immune system, cells put back in patient, stimulate T cells to recognize any cells expressing PAP, attacking cancer cells
  • Fever, chills, headache, flu-like illness, myalgies, HTN, hyperhidrosis, groin pain
33
Q

IL-2:

  • disease
  • toxicity
A
  • renal, melanoma
  • severe capillary leak syndrome (when you give IL-2, youre basically causing sepsis. pressors on protocol, can’t give to everybody)
34
Q

Interferon

  • disease
  • toxicity
A
  • renal, melanoma, CML, hairy cell leukemia
  • flu-like symptoms, fatigue
35
Q

Thalidomide and lenalidomide

  • disease
  • toxicity
A
  • MDS, multiple myeloma
  • teratogenesis, peripheral neuropathy, sedation, constipation, venous thromboembolism
36
Q

Molecularly targeted agents (7)

A
  1. targeted toxins
  2. differentiation agents
  3. proteosome inhibitors
  4. Histone deacetylase (HDAC) inhibitors
  5. Tyrosine Kinase inhibitors (TKIs)
  6. mTOR inhibitors
  7. DNA methyltransferase inhibitors
37
Q

Retinoids: all trans-retinoic acid (ATRA) aka Tretinoin

  • Mech of action
  • uses
  • side effects
A
  • targets PML-retinoic acid receptor (RAR-a) fusion protein (15;17) allowing DNA transcription, inducing differentiation of promyelocytes
  • acute promyelocytic leukemia (APL), aka AML-M3
  • differentiation syndrome, teratogenic
38
Q

in Acute promyelocytic leukemia, where does the cell get “stuck” in differentiation?

A

gets stuck at “neutrophil promeyelocyte” stage: in between myeloblast and N. myelocyte

39
Q

Differentiation Syndrome: describe the scenario and common mistake for treatment

A

after getting treated with ATRA/tretinoin for APL:

on day 4, higher white count, now the differentiatl has changed such that you have 90% normal cells, indicating that you’ve had differentiation. But x-ray shows bif fluffy infiltrate on xray, short of breath, hypoxic

Common mistake is to think the patient has fluid overload, and to give lasix/diuertic. This is WRONG. The patient has differentiation syndrome: more mature cells, they’re having problems, so you need to give high dose steroids

40
Q

Arsenic trioxide

  • mech of action
  • disease
  • side effects
A
  • induced degradation of PML-RARa fusion protein
  • apoptosis via mitochondrial-dependent pathway
  • disease: APL aka AML-M3
  • side effects: differentiation syndrome, prolonged QTc, neuropathy, hyperglycemia, musculoskeletal pain
41
Q

List the 4 important tyrosine kinase inhibitors

A
  • imatinib
  • erlotinib
  • crizotinib
  • sunitinib
42
Q

Imatinib mechanism of action

A

inhibits constitutively active bcr/abl (9,22/philadelphia chromosome) tyrosine kinase, which inhibits proliferation and causes apoptosis

43
Q

diseases treated with Imatinib

A

CML (brc-abl)

Ph+ Acute lymphocytic leukemia (ALL)

GIST (c-kit) = gastrointestinal stromal tumor)

dermatofibrome protuberans (PDGFR)

44
Q

Side effects of Imatinib

A

edema, nausea/vomiting, muscle cramps, diarrhea, rash

45
Q

Similar agents to Imatinib

A

Nilotinib

bcr-abl, c-kit, PDGFR-B - CML

prolongs QTc

_Dasatinib _

bcr-abl, c-kid, PDGFR-B, src -CML, Ph+ ALL

pleural effusions

46
Q

Erlotinib

mechanism of action

A

inhibits intracellular phosphorylation of tyrosine kinase associated with EGFR

47
Q

Erlotinib:

Diseases

A

Non-small cell lung cancer (NSCLC), pancreatic cancer

48
Q

Side effects of erlotinib

A

rash, diarrhea, anorexia, dyspnea, cough, nausea/vomiting

49
Q

Similar agents to Erlotinib

A

Lapatinib (also targets erbB2)- Her2+ breast cancer

hand-foot syndrome

50
Q

Crizotinib

Mechanism of action

A

Targets ATP-binding pocket of constitutively active TK of fusion gene between EML4 and ALK (anaplastic lymphoma kinase)

51
Q

Crizotinib:

Disease

A

Metastatic NSCLC (EMLL4-ALK gene+)

clinical trials in anaplastic large cell lyphoma and neuroblastoma

52
Q

Side effects of crizotinib

A

edema, fatigue, increased liver enzymes, anorexia

53
Q

Sunitinib

mechanism of action

A

inhibits TKs implicated in metastasis, cell growth and angiogenesis, inhibits phosphorylation (PDGFRa, PDGFRB, VEGFR1, 2, and 3, KIT, FLT3, RET)

54
Q

Sunitinib:

Diseases

A

Renal cell carcinoma, gastrointestinal stromal tumor (GIST), pancreatic neuroendocrine tumor (PNET)

55
Q

Sunitinib side effects

A

fatigue, diarrhea, neutropenia, stomatitis, hand-foot syndrome, thyroid dysfunction

MOD 3 (19 decks)

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