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MBBS II HIS > L18,19 - Cytotoxic Drugs in the Treatment of Cancer I & II > Flashcards

L18,19 - Cytotoxic Drugs in the Treatment of Cancer I & II Flashcards

1
Q

5 features of Cancer cells?

A
  • Uncontrolledcell proliferation
  • Decreasedcellular differentiationandloss of‐function
  • Evadingimmune destruction/ surveillance
  • Abilitytoinvade surroundingtissue
  • Metastasis
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2
Q

What is the significance of cancer heterogeneity?

A

Heterogeneity = many tumour cells with different proliferative mechanisms and cell lines

> > need drugs with different MoA to kill all tumour cells

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3
Q

List 6 modalities of treating cancer?

A
  • Surgery
  • RadiationTherapy
  • Chemotherapy
  • HormonalTherapy
  • TargetedTherapy
  • Immunotherapy
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4
Q

Explain why tumour growth plateaus up to a certain size?

A

Decrease nutrient and insufficient space because of limited vascularization (angiogenesis cannot keep up with growth rate)

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5
Q

What are the goals and principles of cancer treatment? exam

A

Improve survival and QoL

1) Cure: eradicate every neoplastic cell = long-term, disease-free survival
2) Control disease: stop the cancer from enlarging and spreading = extend survival, QoL
3) Palliation: alleviate symptoms, avoid life-threatening toxicity= QoL

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6
Q

Earliest chemotherapy drug?

A

Injected mustine to treat Hodgkin’s lymphoma (1950s)

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7
Q

Difference between palliative and curative chemotherapy?

A

Palliative = transient remission, extend survival but eventually deadly

Curative = reduce tumour burden by radiation +/- surgery until micrometastasis is impossible

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8
Q

Difference between neoadjuvant and adjuvant chemotherapy?

A

Neoadjuvant = reduce tumor burden before surgery / radiation

Adjuvant = short course of high-dose drug therapy after radiation / surgery to kill residual cells, prevent recurrence

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9
Q

What chemotherapy strategies are used for relapse/ unresponsive cancers?

A

Salvage therapy: curative high-dose

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10
Q

What are the 2 typical phases of chemotherapy?

A

Induction therapy = high dose to induce complete response to start regimen

Maintenance = low-dose, long-term for complete remission/ delay regrowth

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11
Q

List 6 common side effects of chemotherapy?

A

Affect rapidly dividing cells

  • Nauseaandvomiting
  • Alopecia(hairloss)
  • Fatigue
  • Mucositis
  • Myelosuppression
  • Neurotoxicity
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12
Q

Explain how chemotherapy induces nausea and vomiting?

A

CNS: directly activate the medullary chemoreceptor trigger zone / vomiting center

GI: Release serotinin > stimulate 5-HT3 in CNS

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13
Q

Drug given to limit nausea and vomiting from chemotherapy?

A

5‐HT3 receptorblockers: Ondansetron

single dose, long duration of action

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14
Q

Difference between inherited, acquired and multidrug resistance to chemotherapy?

A 
Inherited = intrinsic (i.e. melanoma) 
Acquired = Tumour mutation against cytotoxicity 
Multidrug = Amplified gene for efflux pump (P-glycoprotein)
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15
Q

Which chemotherapy drug is highly carcinogenic?

A

Alkylating agent

> > Treatmentinducedtumors

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16
Q

List 4 advantages of drug combination in chemotherapy.

A

1) Maximal cell killing within tolerance
2) Kill Wider range of cell lines (heterogeneity)
3) Prevent resistance development
4) Reduce dose of each agent with similar dose-limiting toxicities

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17
Q

Give one example of chemo drug combo.

A 
CHOP = 
 Alkylating agent (cyclophosphamide) 
 Topoisomerase II inhibitor (doxorubicin)
  Anti-microtubule (vincristine) 
 Prednisone
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18
Q

Define the phases of cell cycle?

A

G1, S, G2 and M phases

M phase: 
Prophase
Metaphase
Anaphase
Telophase
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19
Q

Describe the cellular events that occur in Prophase and Metaphase.

A

 Prophase: nucleolus disappears, chromatin condenses, mitotic spindle begins to form

 Metaphase: nuclear envelope fragments, spindle is complete, chromosomes are aligned in the center of the cell

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20
Q

Describe the cellular events that occur in Anaphase and Telophase.

A

 Anaphase: chromatids of each chromosome separate, daughter chromosomes move to opposite ends of the cell

 Telophase: daughter nuclei form, cytokinesis begins

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21
Q

Classify chemotherapy drugs by cell-cycle specificity and which cancers are targeted?

A
  1. Cell-cycle specific = High-growth-fraction malignancies i.e. haematologic cancers
  2. Cell-cycle non-specific = Both low and high growth fraction malignancies
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22
Q

Give examples of cell-cycle specific chemo drugs?

A

 G0, G1: Hormonal drugs, (paclitaxel)

 S: antimetabolites (e.g. 5-fluorouracil, hydroxyurea, azathioprine, Mycophenolate mofetil), Topoisomerase I,II inhibitors (Topotecan, Teoposide), Mitotic inhibitors

 G2: Mitotic inhibitors, Taxanes, Bleomycin

 M: vinca alkaloids (e.g. vincristine)

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23
Q

Classify chemo drugs based on MoA?

A

Cytotoxic drugs:

  • Alkylating agents
  • Antimetabolites
  • Cytotoxic antibiotics
  • Plant derivatives

Hormones

Miscellaneous

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24
Q

3 classes of chemo drugs that are cell- cycle/ S-phase specific?

A
  • Anti‐metabolites&raquo_space; S phase
  • Mitoticinhibitors > Metaphase, Anaphase
  • Topoisomeraseinhibitors > S phase
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25
Q

General MoA of anti-metabolites?

A

Synthetic, stucturally related to endogenous Purine, Pyrimidine, Folates

> > disrupt availability of normal purine / pyrimidine nucleotide precursors

> > disrupt DNA/RNA synthesis

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26
Q

General MoA of mitotic inhibitors?

A

Affect equilibrium between polymerized and depolymerized microtubules in mitotic spindle in metaphase

> > fail anaphase in mitosis

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27
Q

General MoA of topoisomerase inhibitors?

A

Inhibit topoisomerases from religating DNA strands after cleavage

> > fail unwinding and winding of DNA

> > fail DNA replication

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28
Q

Distinguish the general MoA between topoisomerase I and II inhibitors?

A 
I = Induces transient DNA single-strand breaks 
II = induce DNA double-strand breaks
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29
Q

4 classes of drugs that are cell-cycle non-specific?

A
  • Alkylatingagents
  • Anti‐tumorantibiotics
  • Hormoneantagonists
  • Monoclonalantibodies
30
Q

General MoA of alkylating agents?

A

Form highly reactive electropihilic species

> > covalently bind alkyl groups onto nucleophilic sites (e.g.guanine base of DNA ) of cellular macromolecules (e.g. DNA, protein)

> > abnormalbasepairing,DNAbreakage(scission)andcross‐linking

31
Q

List 2 anti-tumour antibiotics? Are they cell cycle specific or not?

A

Anthracyclines: doxorubicin (DOX, Adriamycin), daunorubicin (DNR)

isolatedfromvariousStreptomycesbacteria

cell‐cyclenonspecific

32
Q

MoA of Doxorubicin. (3) exam

A

1) Intercalatingbetweenbasepairsof DNA/RNA
2) InhibitingtopoisomeraseIIenzyme»preventingtherelaxationof supercoiledDNA
3) formsuperoxideionsand hydrogenperoxide via (CYP450 reductase)&raquo_space; single‐strandbreaksinDNA

33
Q

Admin and PK of Doxorubicin. exam

A

 Intravenous administration
 Inactive in GI tract
 Extensive hepatic metabolism
 Majority excreted through bile

34
Q

Indication, ADR of Doxorubicin? What drug given to alleviate ADR? exam

A

 Sarcomas
 Variety of carcinomas (include breast, lung)
 Acute lymphocytic leukemia, lymphomas

generate free radicals + lipid peroxidation cause CARDIOTOXICITY

Give iron-chelator dexrazoxane

35
Q

2 types of tumours that are steroid hormone sensitive?

A

 Hormone-responsive – tumor regresses following treatment with specific hormone;

 Hormone-dependent – tumor regresses following removal of hormonal stimulus

Could be both

36
Q

List 2 SERMs.

A

Tamoxifen

Raloxifene

37
Q

Indication, MoA of Tamoxifen?

A

first-line for advanced / metastatic estrogen receptor-positive breast cancer + reduction in contralateral breast cancer + prophylaxis for high risk breast CA

Binding to intracellular estrogen receptor in target cells: block natural estrogen-receptor complex binding to chromatin for gene transcription

38
Q

ADR of Tamoxifen?

A

weakestrogenic activity:
 Endometrial cancer
 Thromboembolic events (stroke, pulmonary embolism)
 Cataract formation

hot flushes, nausea and vomiting

39
Q

Why is Raloxifene a better SERM than Tamoxifen?

A

Estrogen effect in bone = prevent osteroporosis

No increase in endometrial cancer, vag bleeding

40
Q

List some cell targets in cancers. Give examples of drugs.

A
  1. Altered metabolic enzymes (L-asparaginase)
  2. Cell surface receptors (Herceptin against HER2 in breast CA)
  3. Altered biological processes i.e. angiogenesis (VEGFR inhibitor)
  4. Altered intracellular signalling (Gleevec vs CML)
41
Q

List some actions of antibodies against cancer cells?

A

 Recruit natural effectors (ADCC)

 Neutralize growth factors (e.g. VEGF)

 Block receptors / signal transduction

 Stimulate apoptotic signaling

42
Q

List 3 synthetic antibodies against cancers. Summarize their functions.

A

Rituximab = Anti- CD20 on malignant B lymphocytes + normal cells

Bevacizumab = inhibit vascular endothelial growth factor (VEGF) effects = block angiogenesis

Cetuximab = block epidermal growth factor receptor (EGFR) = block cell prolif. and angiogenesis

43
Q

MoA of Trastuzumab/ Herceptin?

A
  1. Binds to extracellular domain of HER-2 growth receptor (amplified in 30% breast CA) > block dimerization and signalling > no proliferation
  2. Activate ADCC
44
Q

Admin, Preparation and 1 serious ADR of Herceptin.

A

IV, no BBB pen.

Herceptin + Paclitaxel for breast CA

Congestive heart failure

45
Q

List 3 classes of alkylating agents?

A

Nitrogen mustards: Cyclophosphamide***, ifosfamide

Nitrosoureas: carmustin, lomustin

Cisplatin

46
Q

MoA of Nitrogen mustards: Cyclophosphamide and Ifosfamide?

A

pro‐drugs:
cytotoxicafterhydroxylationbyCYP450&raquo_space;> phosphoramidemustard:
1. Covalent bond with nucleophilic groups in cell macromolecules
2. Base mis-pairing, DNA breakage + cross-linking = Mutagenic

47
Q

Admin and 3 major ADR of Cyclophosphamide/ Ifosfamide?

A

Oral or IV
Cross BBB

Carcinogenic
Myelosuppression
HAEMORRHAGIC CYCTITIS (fibrosis of bladder)

48
Q

Admin, indication of nitrosoureas?

A

Oral or IV

highly lipophilic(lipid soluble), cross BBB

Brain tumours

49
Q

Structure, indication, metabolism of Cisplatin?

A

heavymetalplatinumcomplex

everysolidtumorandlymphoma

metabolizedintheliverandexcreted intheurine (not cross BBB)

50
Q

MoA and ADR of cisplatin?

A

MoA: Cisplatin bind to Purines and crosslink&raquo_space; Cisplatin-DNA adduct&raquo_space; replication arrest, cell-cycle arrest, apoptosis

ADR = severe nausea and vomiting, nephrotoxicity

51
Q

MoA of Methotrexate (Anti-metabolite).

A

Active transport in&raquo_space; Polyglutamated** to stay inside

blockingactivesiteofdihydrofolate reductase(DHFR)**

> > DHFR Cannot reduce folic acid

> > No reduced folic acid as co-enzyme for nucleotide production

52
Q

Indication, rescue therapy for Methotrexate?

A
  • ALL,Burkitt’slymphoma,breastcancer,headandneckcarcinoma

(+ treatinflammatorydisease, rheumatoidarthritisandpsoriasis)

  • Leucovorin, activeformoffolicacid
53
Q

Admin (4) and PK of methotrexate?

A

IV, IM, Intrathecal, oral

excretedintheurinemostlyas unchangeddrug

54
Q

2 severe ADR of MTX?

A

Crystalluria (7 hyroxymethotrexate) > nephrotoxicity**

MTX lung**

55
Q

Name 2 purine antagonists and common precursor?

A

6-mercaptopurine (6-MP) (Adenine)

6-thioguanine (6-TG) (Guanine)

Common precursor = Azathioprine

56
Q

Admin, indication of purine antagonists?

A

ALL, pediatric non-hodgkin’s lymphoma

Oral, IV

57
Q

MoA of 6-mercaptopurine and 6- thioguanine?

A

Purine salvage synthesis:

1) HGPRT convert 6-MP to TIMP&raquo_space;
TIMP inhibit de-novo purine ring biosynthesis
+ Block formation of GMP, AMP, XMP from IMP precursor
+ Incorporate into DNA/RNA as false nucleotide

2) HGPRT convert 6-TG to 6-tGMP&raquo_space;
incorporate into RNA, DNA as false nucleotide

58
Q

Explain why allopurinol causes accumulation of 6-MP?

A

6-MP –[Xanthine oxidase] –> inactivated into 6-thiouracil

6-MP cannot be converted to TIMP/ 6-TG&raquo_space; cannot exert effects

59
Q

major ADR of 6-MP/Azathioprine?

A

myelosuppression

60
Q

Name one pyrimidine antagonist and MoA?

A

5‐fluorouracil

Converted to fluorouridinemonophosphate (5‐FUMP) &raquo_space; further form:

1) fluorouridine triphosphate/ 5‐FUTP» incorporatedin DNA/RNA
2) 5 - fluorodeoxyuridinemonophosphate/ 5-FdUMP» inhibit thymidylatesynthase&raquo_space; block DNA synthesis

61
Q

Name 1 synergistic drug to 5-fluorouracil, Admin, metabolism of 5-FU?

A

leucovorincalcium (folate): increase inhibition effect on thymidylate synthase

IV mostly, Intra-arterial into hepatic artery, penetrate BBB

Metabolized in liver, excreted by kidneys and lungs

62
Q

List 2 mitotic inhibitor classes and examples?

A
  • Vinca alkaloids: e.g. Vincristine, Vinblastine
  • Taxanes:
    a) Paclitaxel
    b) Docetaxel
63
Q

MoA of Vinca alkaloids?

A

GTP-dependent binding to tubulin

> > block tubulin polymerization

> > dysfunctional mitotic spindle in metaphase

> > Dissolution of spindle + chromosome segregation, apoptosis

64
Q

Resistance mechanism, metabolism, ADR of Vinca alkaloids?

A

Efflux by P-glycoprotein

Cytochrome p450 metabolism in liver (extensive)

Vinblastine = Myelosuppression, 
Vincristine =  peripheral neuropathy, 
Vinorelbine = granulocytopenia
65
Q

Admin, indication and metabolism of Taxanes (Paclitaxel(Taxol) or Docetaxel(Taxotere))?

A

IV

Paclitaxel = ovarian,breast, small‐cellandlarge‐celllungcancers, andKarposi'ssarcoma
Docetaxel = NSCLC,breast,prostate,gastriccancer

Long t1/2, liver metabolism, biliary excretion

66
Q

ADR of Taxanes?

A

Both: HYPERSENSITIVITY + NEUTROPENIA

Paclitaxel =myelosuppression,serious allergicreaction**,nausea,vomiting, neutropenia

Docetaxel = neutropenia,hypersensitivity,EDEMA (C/O CVS DISEASES), rash, neuropathy

**precede Paclitaxel with dexamethasone, diphenhydramine/ H1+H2blocker

67
Q

MoA of Taxanes?

A

bindreversiblytothetubulinsubunit

> > PROMOTE polymerizationand stabilization (opposite to vinca alkaloids)

> > accumulationofnonfunctional microtubules, cannot depolymerize

> > chromosomescannotsegregate

> > cell frozen in metaphase.

68
Q

Mechanism of resistance to Taxanes?

A

amplifiedP-glycoproteinortubulinmutation

69
Q

Examples of topoisomerase I and II inhibitors?

A

TopoisomeraseIinhibitors =irinotecanandtopotecan

TopoisomeraseIIinhibitors= etoposideand teniposide

70
Q

Indication and MoA of topoisomerase I inhibitor?

A

Resistant metastatic ovarian cancer
Small cell lung cancer
Colon/ rectal carcinoma

Bind to and Stabilize natural topoisomerase-I/DNA complex&raquo_space; Preventthereligationof thesingle‐strandbreaks&raquo_space; fail cell replication

71
Q

Indication and MoA of etoposide/ teniposide (topoisomerase-II inhibitor)

A

oat-cell lung carcinoma
Testicular carcinoma
ALL

Bind to and Stabilize natural topoisomerase-II/DNA complex
» Cause irreversible** double stranded breaks in DNA
» inhibit DNA synthesis

Topoi-I inhibitor only causes transient single strand break

MBBS II HIS (30 decks)

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