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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
General MoA of anti-metabolites?
Synthetic, stucturally related to endogenous Purine, Pyrimidine, Folates >> disrupt availability of normal purine / pyrimidine nucleotide precursors >> disrupt DNA/RNA synthesis
26
General MoA of mitotic inhibitors?
Affect equilibrium between polymerized and depolymerized microtubules in mitotic spindle in metaphase >> fail anaphase in mitosis
27
General MoA of topoisomerase inhibitors?
Inhibit topoisomerases from religating DNA strands after cleavage >> fail unwinding and winding of DNA >> fail DNA replication
28
Distinguish the general MoA between topoisomerase I and II inhibitors?
``` I = Induces transient DNA single-strand breaks II = induce DNA double-strand breaks ```
29
4 classes of drugs that are cell-cycle non-specific?
* Alkylating agents * Anti‐tumor antibiotics * Hormone antagonists * Monoclonal antibodies
30
General MoA of alkylating agents?
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) >> abnormal base pairing, DNA breakage (scission) and cross‐linking
31
List 2 anti-tumour antibiotics? Are they cell cycle specific or not?
Anthracyclines: doxorubicin (DOX, Adriamycin), daunorubicin (DNR) isolated from various Streptomyces bacteria cell‐cycle nonspecific
32
MoA of Doxorubicin. (3) *exam*
1) Intercalating between base pairs of  DNA/RNA  2) Inhibiting topoisomerase II enzyme>> preventing the relaxation of  supercoiled DNA 3) form superoxide ions and hydrogen peroxide via (CYP450 reductase) >> single‐strand breaks in DNA
33
Admin and PK of Doxorubicin. *exam*
 Intravenous administration  Inactive in GI tract  Extensive hepatic metabolism  Majority excreted through bile
34
Indication, ADR of Doxorubicin? What drug given to alleviate ADR? *exam*
 Sarcomas  Variety of carcinomas (include breast, lung)  Acute lymphocytic leukemia, lymphomas generate free radicals + lipid peroxidation cause CARDIOTOXICITY Give iron-chelator dexrazoxane
35
2 types of tumours that are steroid hormone sensitive?
 Hormone-responsive – tumor regresses following treatment with specific hormone;  Hormone-dependent – tumor regresses following removal of hormonal stimulus Could be both
36
List 2 SERMs.
Tamoxifen | Raloxifene
37
Indication, MoA of Tamoxifen?
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
ADR of Tamoxifen?
weak estrogenic  activity:  Endometrial cancer  Thromboembolic events (stroke, pulmonary embolism)  Cataract formation hot flushes, nausea and vomiting
39
Why is Raloxifene a better SERM than Tamoxifen?
Estrogen effect in bone = prevent osteroporosis No increase in endometrial cancer, vag bleeding
40
List some cell targets in cancers. Give examples of drugs.
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
List some actions of antibodies against cancer cells?
 Recruit natural effectors (ADCC)  Neutralize growth factors (e.g. VEGF)  Block receptors / signal transduction  Stimulate apoptotic signaling
42
List 3 synthetic antibodies against cancers. Summarize their functions.
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
MoA of Trastuzumab/ Herceptin?
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
Admin, Preparation and 1 serious ADR of Herceptin.
IV, no BBB pen. Herceptin + Paclitaxel for breast CA Congestive heart failure
45
List 3 classes of alkylating agents?
Nitrogen mustards: Cyclophosphamide***, ifosfamide Nitrosoureas: carmustin, lomustin Cisplatin
46
MoA of Nitrogen mustards: Cyclophosphamide and Ifosfamide?
pro‐drugs: cytotoxic after hydroxylation by CYP450 >>> phosphoramide mustard: 1. Covalent bond with nucleophilic groups in cell macromolecules 2. Base mis-pairing, DNA breakage + cross-linking = Mutagenic
47
Admin and 3 major ADR of Cyclophosphamide/ Ifosfamide?
Oral or IV Cross BBB Carcinogenic Myelosuppression HAEMORRHAGIC CYCTITIS (fibrosis of bladder)
48
Admin, indication of nitrosoureas?
Oral or IV highly lipophilic(lipid  soluble), cross BBB Brain tumours
49
Structure, indication, metabolism of Cisplatin?
heavy metal platinum complex   every solid tumor and lymphoma metabolized in the liver and excreted  in the urine (not cross BBB)
50
MoA and ADR of cisplatin?
MoA: Cisplatin bind to Purines and crosslink >> Cisplatin-DNA adduct >> replication arrest, cell-cycle arrest, apoptosis ADR = severe nausea and vomiting, nephrotoxicity
51
MoA of Methotrexate (Anti-metabolite).
Active transport in >> Polyglutamated** to stay inside blocking active site of dihydrofolate reductase(DHFR)** >> DHFR Cannot reduce folic acid >> No reduced folic acid as co-enzyme for nucleotide production
52
Indication, rescue therapy for Methotrexate?
- ALL, Burkitt’s lymphoma, breast cancer, head and neck carcinoma (+ treat inflammatory disease,  rheumatoid arthritis and psoriasis) - Leucovorin, active form of folic acid
53
Admin (4) and PK of methotrexate?
IV, IM, Intrathecal, oral excreted in the urine mostly as  unchanged drug
54
2 severe ADR of MTX?
Crystalluria ( 7 hyroxymethotrexate) > nephrotoxicity** MTX lung**
55
Name 2 purine antagonists and common precursor?
6-mercaptopurine (6-MP) (Adenine) 6-thioguanine (6-TG) (Guanine) Common precursor = Azathioprine
56
Admin, indication of purine antagonists?
ALL, pediatric non-hodgkin's lymphoma Oral, IV
57
MoA of 6-mercaptopurine and 6- thioguanine?
Purine salvage synthesis: 1) HGPRT convert 6-MP to TIMP >> 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 >> incorporate into RNA, DNA as false nucleotide
58
Explain why allopurinol causes accumulation of 6-MP?
6-MP --[Xanthine oxidase] --> inactivated into 6-thiouracil 6-MP cannot be converted to TIMP/ 6-TG >> cannot exert effects
59
major ADR of 6-MP/Azathioprine?
 myelosuppression
60
Name one pyrimidine antagonist and MoA?
5‐fluorouracil Converted to fluorouridine monophosphate   (5‐FUMP) >> further form: 1) fluorouridine triphosphate/ 5‐FUTP >> incorporated in  DNA/RNA 2)  5 - fluorodeoxyuridine monophosphate/ 5-FdUMP >> inhibit thymidylate synthase >> block DNA synthesis
61
Name 1 synergistic drug to 5-fluorouracil, Admin, metabolism of 5-FU?
leucovorin calcium (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
List 2 mitotic inhibitor classes and examples?
- Vinca alkaloids: e.g. Vincristine, Vinblastine - Taxanes: a) Paclitaxel b) Docetaxel
63
MoA of Vinca alkaloids?
GTP-dependent binding to tubulin >> block tubulin polymerization >> dysfunctional mitotic spindle in metaphase >> Dissolution of spindle + chromosome segregation, apoptosis
64
Resistance mechanism, metabolism, ADR of Vinca alkaloids?
Efflux by P-glycoprotein Cytochrome p450 metabolism in liver (extensive) ``` Vinblastine = Myelosuppression, Vincristine = peripheral neuropathy, Vinorelbine = granulocytopenia ```
65
Admin, indication and metabolism of Taxanes (Paclitaxel(Taxol) or Docetaxel(Taxotere))?
IV ``` Paclitaxel = ovarian, breast,  small‐cell and large‐cell lung cancers,  and Karposi's sarcoma Docetaxel =  NSCLC, breast, prostate, gastric cancer ``` Long t1/2, liver metabolism, biliary excretion
66
ADR of Taxanes?
Both: HYPERSENSITIVITY + NEUTROPENIA Paclitaxel = myelosuppression, serious allergic reaction**, nausea, vomiting, neutropenia Docetaxel = neutropenia, hypersensitivity, EDEMA (C/O CVS DISEASES), rash, neuropathy **precede Paclitaxel with dexamethasone,  diphenhydramine/ H1+H2blocker
67
MoA of Taxanes?
bind reversibly to the tubulin subunit >> PROMOTE polymerization and  stabilization (opposite to vinca alkaloids) >> accumulation of nonfunctional  microtubules, cannot depolymerize >> chromosomes cannot segregate >> cell frozen in metaphase. 
68
Mechanism of resistance to Taxanes?
amplified P-glycoprotein or tubulin mutation
69
Examples of topoisomerase I and II inhibitors?
TopoisomeraseI inhibitors = irinotecan and topotecan TopoisomeraseII inhibitors = etoposide and  teniposide 
70
Indication and MoA of topoisomerase I inhibitor?
Resistant metastatic ovarian cancer Small cell lung cancer Colon/ rectal carcinoma Bind to and Stabilize natural topoisomerase-I/DNA complex >> Prevent the religation of  the single‐strand breaks >> fail cell replication
71
Indication and MoA of etoposide/ teniposide (topoisomerase-II inhibitor)
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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