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Pharmacology > Cancer & Chemotherapy > Flashcards

Cancer & Chemotherapy Flashcards

1
Q

what is neoplastic conversion?

A

chemical alteration to DNA –> mutant DNA

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2
Q

neoplastic development and progression

A

neoplastic cell –> growth/promotion

–> differentiated neoplasm–> progression

–>undifferentiated cancer

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3
Q

what are the 4 properties of chemical carcinogens?

A

1- carcinogenesis is dose dependent

2- long lag period between exposure and appearance of tumors (in humans >20 years)

3- carcinogens are subject to activation and degradation

4- active carcinogens are electrophiles (+ charge)

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4
Q

what are human chemical carcinogens?

A

there are at least 20 different well established human carcinogens

MECHLORETHYLAMINE (alkylating agents)
reacts with DNA (nerve gas)

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5
Q

what are the classes of carcinogens?

A

direct acting carcinogen

procarcinogen

epigenic carcinogen

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6
Q

what are subclasses of epigenetic carcinogens?

A

1- immunosuppressors- Benzene

2- hormones- DES

3- solid state carcinogens- Asbestos

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7
Q

what are oncogenes?

A

genes that encode for transforming proteins that can cause cancer.

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8
Q

what are oncogenes derived from?

A

derived from the mutation of PROTO-ONCOGENES: genes in normal cells that encode for proteins involved in cellular regulations, including:

  • G proteins
  • TYROSINE-SPECIFIC KINASES
  • other protein kinases
  • growth factors
  • transcription regulators

usually these cells are dormant, so there has to be an activation of the cells to grow.

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9
Q

what are anti-oncogenes?

A

tumor supressor genes

these are also referred to as “growth suppressor genes” in normal cells

These proteins suppress cell growth and division mutation leads to a loss of the ability to restrain cell growth and division the anti-oncogene product is a mutant protein that is inactive as a growth suppressor

**similar to oncogenes BUT get mutations that INactivate

ex: brca gene in breast cancer

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10
Q

what are childhood tumors with high cure rates?

A 
acute lymphocytic leukemia
Burkitt's lymphoma
Ewings' sarcoma- bone tumor
Retinoblastoma
Wilms' tumor- kidney tumor
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11
Q

what are adult tumors with high cure rates?

A

Hodgkin’s disease
Non-hodgkin’s lymphomas
Trophoblastic choriocarcinoma
Testicular and ovarian germ cell cancers

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12
Q

what is common about all of the tumors with high cure rates?

A

they are all fast growing

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13
Q

what are the mechanisms of chemotherapy?

A

cancer drugs inhibit cell proliferation

tumor cells are rapidly proliferating and thus especially sensitive

other rapidly proliferating tissues (bone marrow, hair, GI and oral mucosa) are adversely affected

Filgrastim (Neupogen)- granulocyte colony stimulating factor used to increase WBCs

nausea and vomiting are common
drugs can be used to prevent nausea

Resistance can occur with all cancer drugs.

useful to employ multiple agents if they act on different parts of the cell cycle

use different agents with different toxicities

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14
Q

what is resistance?

A

resistance can occur with all cancer drugs

P-glycoprotein resides in cell membranes that pump out toxins may be responsible for resistance of cells to many anticancer drugs

bc cancer cells mutate so fast, eventually they develop a mechanism for resistance

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15
Q

how can we get around resistance?

A

use of multiple agents

try to get drugs that work in different ways- so that when we give a drug their activities are enhancing each other

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16
Q

what is combination therapy?

A

using different drugs with different toxicities

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17
Q

what is doxirubicin?

A

antibiotic- cardiac toxicity

long term–> valve damage

dosage: 25 mg/m2, IV
schedule: days 1, 15
repeat cycle every 28 days

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18
Q

most anticancer drugs are:

A

CYTOTOXIC and BLOCK CELL PROLIFERATION

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19
Q

what are the 3 phases of the cell cycle?

A

S phase: DNA synthesis
M phase: mitosis (cell division)
G phase: resting

drugs that work in the S phase are antimetabolites

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20
Q

what is growth fraction?

A

proportion of cells actively proliferating

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21
Q

tumor growth rate is initially…?

A

rapid (exponential)

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22
Q

tumor growth rate slows due to?

A

slows due to decrease in growth fraction and an increase in cell loss caused by hypoxia, poor nutrient supply and immunological defenses

23
Q

what are alkylating agents?

what are its adverse effects?

A

transfer alkyl groups to DNA, inhibiting cell division

cell-cycle nonspecific

adverse effects: bone marrow suppression, nausea and vomiting

some are potent vesicants

example drugs:

  • mechlorethamine (Mustargen)
  • ifosfamide (Ifex)
24
Q

what are platinum coordination compounds?

A

metal complexes

mechanism similar to alkylating agents

cisplatin used for neoplasms of testies, lymph tissue or ovaries

highly effective, but limited by nephrotoxicity (poisonous effect)

carboplatin (Paraplatin) used for ovarian cancers

25
Q

what are antimetabolites?

what are adverse effects?

A

inhibit key metabolic steps required for DNA synthesis:

  • folic acid synthesis
  • purine synthesis
  • pyrimidine synthesis

act during S phase of cell cycle

some also used as immunosuppressive

adverse effects: immunosuppressant, GI lesions, alopecia, bone marrow depression, skin rash

26
Q

what are vinca alkaloids?

what are adverse effects?

A

derived from periwinkle plant

inhibit mitosis: acts during M phase of cell cycle

used especially in breast cancer and choriocarcinoma

Adverse effects: bone marrow suppression, alopecia, GI lesions, neurotoxicity

currently available: vincristine and vinblastine

27
Q

what are cytotoxic antibiotics and synthetics?

adverse effects?

A

bind to DNA to inhibit RNA synthesis: G2 phase of cell cycle

adverse effects: visual toxicity: additional unique, drug specific side effects

example: bleomucin (lung fibrosis)

28
Q

hormones:

A

ANDROGENS:
fluoxymesterone or testolactone- for breast cancer

ANTI-ANDROGENS:
flutamide and bicalutamide- for advanced prostatic cancer in combo with LHRH agonist such as Leuprolide

PROGESTINS- for advanced breast cancer

ANTI-ESTROGENS (TAMOXIFEN)- for breast cancer

29
Q

what is tamoxifen?

A

anti estrogen hormone for breast cancer

30
Q

what is used to block the cancer cell signaling?

A

TYROSINE KINASE INHIBITORS

monoclonal antibodies

cox-2 inhibitors

thalidomide

31
Q

what do tyrosine kinase receptors do?

A

transduce signals that direct:

  • growth
  • division
  • migration
  • synthesis
  • apoptosis (cell death)
32
Q

what is VEGF?

A

vascular endothelial growth factor

33
Q

the 6 members of the VEGF family bind with..

A

different affinities to specific receptors

angiopoietin-1 activates the receptor and leads to vessel stability, whereas angiopoietin-2 binds to the receptor, competitively inhibits ang-1 and leads to vessel instability

34
Q

what is angiogenesis?

A

generation and growth of new blood vessels

35
Q

in the absence of blood supply, tumor growth is limited to:

A

1-2 mm3

36
Q

in response to hypoxia, tumors…

A

tumors secrete growth factors to promote angiogenesis

37
Q

what is EGF?

A

epidermal growth factor

38
Q

what is FGFs?

A

fibroblast growth factor, acidic or basic)

39
Q

what is PDEGF?

A

platelet-derivate endothelial growth factor

40
Q

what is PIGF?

A

placenta growth factor

41
Q

tumor angiogenesis and neovasculature:

A

1- tumors less than 1 mm3 receive oxygen and nutrients by diffusion from host vasculature

2- larger tumors require new vessel network. tumor secretes angiogenic factors that stimulate migration, proliferation and neovessel formation by endothelial cells in adjacent established vessels

3- newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth

42
Q

EGFR- TK inhibitor:

A

proliferation/maturation (tumor increasing in size)

chemotherapy/radiotherapy resistance

angiogenesis (formation of new blood vessels)

metastasis (spreading to other areas of the body)

survival/anti-apoptosis (preventing the cell from dying)

43
Q

what are 3 tyrosine kinase inhibitors?

A

Gefitinib (Iressa)– Her-1 tyrosine kinase

Erlotinib (Trachea)- Her-1 tyrosine kinase

Imatinib (Gleevec)- Bcr-Abl (a tyrosine kinase that is always active in CML)

44
Q

what is Gefitinib (Iressa)?

adverse effects?

A

non-small cell lung cancer
AKA ZD 1839
given orally 250-500 mg daily

adverse effects:

  • skin rash 72%
  • diarrhea 35%
  • nausea/vomiting
  • myeosuppression
45
Q

what is Erlotinib (Tarceva)??

adverse effects?

A

locally advanced or metastatic NSCLCa

investigational use: head & neck squamous cell carcinoma and advanced ovarian CA

adverse effects:

  • cutaneous toxicity 72-88%
  • diarrhea
  • nausea/vomiting, headache, fatigue, hyperbilirubinemia, myelosuppression, mucositis
46
Q

what is IMATINIB (GLEEVEC) MOA?

A

gleevec was custom designed to treat CML

CML results through a chromosomal rearrangement that fuses two genes together.

this produces an oncogene that encodes an enzyme, a form of tyrosine kinases known as BCR-ABL (a hybrid Bcr-Abl enzyme that is always active)

the abnormal activity of the enzyme causes the over proliferation of WBCs that is the hallmark of CML

47
Q

what are the 3 monoclonal antibodies?

A

Trastuzumab (HERCEPTIN)- anti Her2 mab

Cetuximab (Erbitux)- anti EGRF mab

Bevacizumab (AVASTIN)- anti VEGF mab

48
Q

what is HERCEPTIN used for?

adverse effects?

A

FDA approved for the treatment of Her2 positive metastatic breast cancer

adverse effects:

  • cardiomyopathy
  • anemia/leukopenia
  • rashes
49
Q

what is AVASTIN used for?

adverse effects?

A

FDA approved for the treatment of colorectal carcinoma; used in combo with 5FU

adverse effects:

  • thrombosis
  • hypertension
  • proteinuria
  • bleeding
50
Q

what are cox2 inhibitors and angiogenesis (celecoxib)?

A

cancer cell over express cox2

cox2 induces expression of VEGF through the production of PGE2

cox 2 inhibitors indirectly down regulate the activity of angioneogenic factors such as VEGF

51
Q

what does thalidomide do?

A

thalidomide inhibits angiogenesis by blocking VEGF

decrease the cells’ ability to induce Cox2 expression

most extensive clinical data done on plasma call disorders, specifically

52
Q

what is the efficacy of anti-angiogenic therapy?

A

anti-angiogenic therapy leads to inhibition of tumor growth rather than regression of established tumors

53
Q

what is the effect on tumors of traditional vs. antiangiogenic anticancer therapy?

A

current anticancer therapy may either cause tumor regression or slow the progress of the tumor until failure of therapy

the majority of anti-angiogenic therapy studies show that although the agents do not usually cause regression, they lead to inhibition of tumor growth. anti-angiogenic therapy has the potential to convert an acute disease to a chronic disease

Pharmacology (8 decks)

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