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SBL > Cancer Pharmacology 1 > Flashcards

Cancer Pharmacology 1 Flashcards

1
Q

What is the role of oncogenes and tumor suppressor genes?

A

Oncogenes positively influence tumor development - i.e. Ras.

Tumor suppressors are genes that negatively impact tumor growth - i.e. p53.

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2
Q

What is neoadjuvant chemotherapy?

What is adjuvant chemotherapy?

A

The use of chemotherapy in patients prior to other treatment.

Additional chemotherapy given for a defined period of time after surgery. It helps prevent relapse.

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3
Q

What is primary/inherent chemotherapeutic resistance?

A

Drug resistance by the cancer cell in the absence of prior exposure.

“Genetic instability of cancer” - p53 mutations.

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4
Q

What is acquired chemotherapeutic drug resistance?

A

The development of resistance in response to exposure to a cancer drug.

Genetic change - amplification or suppression of a particular gene.

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5
Q

Where is p-glycoprotein (PGP, MDR1) expressed most?

What does a high baseline [PGP] suggest?
What overexpression cause?

A

Tissues with barrier functions - kidneys, liver, GI tract.
Pharmacological barrier sites - BBB, placenta.

Primary/inherent resistance to natural products.
Acquired drug resistance.

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6
Q

Which cell populations tend to be the most susceptible to adverse-effects of chemotherapy? (5)

A

Non-cancerous proliferating drugs.

  • BM precursors of blood cells (cytopenias, myelosuppression)
  • Intestinal epithelial cells
  • Oral mucosa
  • Gonadal cells
  • Hair follicles (alopecia)
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7
Q

What is the MOA of alkylating agents?

Which cells are most vulnerable?

A

Transfer alkyl groups to DNA leading to DNA cross-linking. The causes an arrest in late G1/early S phase.

Replicating cell are most vulnerable.

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8
Q

What are 3 mechanisms of resistance to alkylating agents?

A

Increased capacity to repair DNA lesions by increasing the activity of DNA repair enzymes.

Decreased cellular transport of the alkylating drugs.

Increased activity of glutathione and glutathione-associated proteins (leads to inactivation).

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9
Q

What are the major side-effects of alkylating agents? (4)

A

Effects at rapidly growing tissue.

  • BM suppression
  • GI tract: diarrhea

N/V/D

Blistering at site of administartion.

Carcinogenic - increased risk of secondary malignancies (AML).

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10
Q

Which alkylating agent crosses the BBB?

A

Carmustine

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11
Q

What is the MOA of antimetabolites?

What cells are most susceptible?

A

They mimic and/or reduce the essential components needed for the formation of DNA, RNA and proteins.
Arrest and/or DNA damage occurs during S phase.

Replicating cells are most susceptible.

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12
Q

What are 3 mechanisms for resistance for antimetabolites?

A

Inhibition of metabolism into active metabolites.

Decreased drug transport.

Decreased polyglutamate metabolites by folyl polyglutamate synthase (FPGS) (important for MTX, pemetrexed, pralatrexate).

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13
Q

What adverse-effects are associated with antimetabolites? (3)

A

Myelosuppression

N/V/D

Hand-foot syndrome: painful erythema and swelling of hands and feet.

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14
Q

What are the unique MOA for Cytarabine (antimetabolic)? (3)

A

It is converted to ara-CTP. Ara-CTP competitively inhibits DNA pol-a and DNA pol-B.

Ara-CTP is incorporated into DNA.

Ara-CTP is incorporated into RNA.

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15
Q

What is the unique MOA of 6-mercaptopurine?

A

It is a purine antagonist. It is metabolized by HGPRT to form 6-thioinosinic acid, which inhibits de novo purine synthesis.
The triphosphate form can be incorporated into RNA or DNA.

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16
Q

What are the 2 general categories of natural products?

A

Tubulin polymerization: disruptive and enhancing.

Topoisomerase inhibitors (1 and 2)

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17
Q

What are the 3 drugs that disrupt tubulin polymerization?

What are the 3 drugs that enhance tubulin polymerization?

A

Disrupt: Vinblastine, Vincristine, Vinorelbine.

Enhance: Paclitaxel, Docetaxel, Cabazitaxel.

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18
Q

What are the 2 topoisomerase 1 inhibitors?

What is the only topoisomaerse 2 inhibitor?

A

Topoisomerase 1: Topotecan, Irinotecan.

Topoisomerse 2: Etoposide.

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19
Q

What are the 2 mechanisms for resistance of natural products?

A

P-glycoprotein mediated drug efflux.

Point mutations in drug binding pockets (i.e. topoisomerase inhibitors).

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20
Q

What are the adverse-effects of natural products? (5)

A

Myelosuppression

N/V

Neurotoxicity - Vincristine

Hypersensitivity - Paclitaxel, Docetaxel

Diarrhea - Topotecan, Irinotecan

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21
Q

What is the one natural product that has a way around resistance due to PGP?

A

Cabazitaxel

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22
Q

What are 3 MOAs associated with antitumor antibiotics and which drug falls into each one?

A

Inhibition of topoisomerase 2, generation of free radicals (DNA damage), DNA intercalation.
-Anthracyclines (Doxorubicin)

Induction of DNA cross-links.
-Mitomycin

DNA fragmentation and single/double strand breaks due to free radical formation.
-Bleomycin

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23
Q

What are 3 mechanisms of resistance to antitumor antibiotics and which mechanisms effect which drugs?

A

Point mutations in topoisomerase 2, suppression of apoptotic signaling.
-Doxorubicin

Increased expression of multidrug resistant efflux pumps.
-Doxorubicin, Mitomycin

Upregulation of bleomycin hydrolase enzyme.

24
Q

What are common adverse-effects of antitumor antibiotics?

A

Myelosuppression

N/V

Free radical-mediated cardiotoxicity
-Doxorubicin

Blue discoloration of nails, sclera and urine
-Mitoxantrone

Pulmonary toxicity
-Bleomycin

25
Q

What adverse-effect is unique to Bleomycin?

A

Pulmonary toxicity

26
Q

What adverse-effect is unique to Mitoxantrone?

A

Blue discoloration of nails, sclera and urine

27
Q

What is seen in the acute form of Doxorubicin induced cardiotoxicity?

What is seen in the chronic form?

A

Acute: occurs within the first 2-3 days. Presents with arrhythmias, pericarditis, myocarditis. It is often transient and asymptomatic.

Chronic: dose-dependent and may lead to DCM-associated HF.

28
Q

What is the MOA of tyrosine kinase and GF inhibitors?

What is the mechanism of resistance?

A

Inhibition of GF receptor signaling and inhibition of tyrosine kinase activity.

Point mutations in drug binding sites.

29
Q

What adverse-effects are associated with tyrosine kinase and GF inhibitors?

A

N/V

Acneform skin rash and hypersensitivity
-Cetuximab

30
Q

What does the tyrosine kinase inhibitor Imatinib inhibit specifically?

What is it the first line therapy for?

A

Inhibits the BCR-ABL oncoprotein.

AML - t(9;22) translocation.

31
Q

What is the unique MOA of Ziv-aflibercept (GF inhibitor)?

A

It is a recombinant fusion protein made of portions of human VEGF-R (a soluble receptor for VEGF and PIGF). Binding of VEGF ligands prevents their interactions with VEGF-R.

It inhibits VEGF-R signaling overall.

32
Q

What are the PD-1 (T-cell) inhibitors? (2)

What is the class MOA?

What cancers are they used to treat? (3)

A

Nivolumab, Pembrolizumab.

Immune checkpoint inhibitors.

Melanoma, non-small cell lung cancer, Hodgkin’s lymphoma.

33
Q

What are the PD-L1 (T-cell) inhibitors? (3)

What is the class MOA?

What cancers are they used to treat? (3)

A

Atezolizumab, Avelumab, Durvalumab.

Immune checkpoint inhibitors.

Bladder cancer, non-small cell lung cancer, Merkel cell skin cancer.

34
Q

What are the adverse-effects of immune checkpoint inhibitors (2 categories)?

A

Fatigue, nausea, loss of appetite, itching

Immune system attack of normal organs.

35
Q

What drug class do the following fall into?

Bis (chlorethyl) amines
Nitrosureas
Non-classic
Platinum analogs

A

Alkylating agents

36
Q

MOA

  • nib
  • mab
A
  • nib: TK inhibitor (BCR-ABL, PDGFR-B tyr kinase and c-kit)

- mab: GF-R inhibitor

37
Q

What is a use of leucovorin in combination with MTX?

A

It helps protect healthy cells from damage due to MTX

38
Q

What drug is associated with significant GI toxicity?

A

5-FU

39
Q

Wat drug is associated with hand-foot syndrome?

A

Pemetrexed

40
Q

What drug is a prodrug? What class is it in?

A

Dacarbazine; alkylating agent.

41
Q

How can methotrexate-resistance develop?

A

Decreased drug transport.

Decreased formation of polyglutamate metabolites by FPGS.

42
Q

How can -trexate-resistance occur?

A

Decreased formation of polyglutamate metabolites by FPGS.

43
Q

Drug class: Cytyrabine

A

Antimetabolites

44
Q

Drug class and MOA: Vinblastine, Vincristine, Vinorelbine

A

Natural product; tubulin disrupters.

45
Q

Drug class and MOA: -taxels

A

Natural products; tubulin enhancers.

46
Q

Drug class and MOA: -tecans

A

Natural products; topoisomerase-1 inhibitors.

47
Q

Drug class and MOA: Etoposide

A

Natural products; topoisomerase-2 inhibitor.

48
Q

A/E: Vincristine

A

Neurotoxicity

49
Q

A/E: Paclitaxel, Docetaxel

A

Hypersensitivity reactions

50
Q

A/E: Topotecan, Irnotecan

A

Diarrhea

51
Q

Doxorubicin MOA:

MOR:

A/E:

A

Inhibition of topoisomerase-2, generation of free radicals and DNA intercalation.

Point mutations in topoisomerase-2.
Increased expression of efflux pumps.

Cardiotoxicity

52
Q

Mitomycin MOA:

MOR:

A

Induction of DNA cross-linking.

Increased expression of efflux pumps.

53
Q

Bleomycin MOA:

MOR:

A/E:

A

DNA fragmentation and single/double-stranded bond breaks due to free radical formations.

Increased expression of bleomycin hydrolase.

Pulmonary toxicity.

54
Q

Cetuximab drug class:

A/E:

A

GF inhibitor.

Acne-like rash and hypersensitivity.

55
Q

MOA and drug class: Nivolumab, Pemprolizumab

A/E:

A

immune checkpoint inhibitors; PD-1 inhibition.

Fatigue, nausea, loss of appetite and pruritis.
Immune system attack of other organs.

56
Q

MOA and drug class: Atezolizumab, Avelumab, Durvalumab

A/E:

A

Immune checkpoint inhibitors; PD-L1 inhibition.

Fatigue, nausea, loss PF appetite and pruritis.
Immune system attack of other organs.

57
Q

What is the MOR of immune checkpoint inhibitors?

A

T-cell function/production problems.

SBL (44 decks)

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