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BIOM 4090 > Unit 09: Cancer drugs > Flashcards

Unit 09: Cancer drugs Flashcards

1
Q

what are alkylating agents?

A

provide antineoplastic properties by transferring an alkyl group to cellular constituents

  • major site of action = DNA where alkyl group attaches at number 7 nitrogen or number 6 oxygen of guanine
  • agents can monoalkylate, cross link two guanines on a single strand or between strands or link guanine to a protein

*all result in failure of proper formation of DNA helix

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2
Q

what types of cells are more sensitive to alkylating agents

A

proliferating cells more sensitive than non proliferating

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3
Q

classes of alkylating agents

A
  • alkylsulfonates, methylenimines, ethylenimines, nitrogen mustards (cyclophophamide), nitrosoureas, triazenes and platinum compounds (cisplatin)
  • Cisplatin is technically not an alkylating agent but also bidns at number 7 nitrogen and cross links DNA so similar MOA
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4
Q

describe the biochemical outcome of guanine alkylation

A
  • guanine alkylation can cause several types of DNA damage
  • nitrogen of mechlorethamine performs a nucleophilic attack on one of its own B carbons, resulting in an unstable intermediate that is highly electrophili
  • nucleophilic N7 guanine reacts with unstable intermediate resulting in alkylated guanine
  • four potential outcomes of initial alkylation all of which cause structural damage to DNA
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5
Q

what is cyclophosphamide

A
  • most commonly used alkylating agent
  • borad spec and less toxic than other drugs
  • taken orally or intravenously, after which a non reactive prodrug is converted to an alkylating agent by liver cytochrome P450 enzymes
  • can use alone or in combo with toher therapeutics to treat lymphomas, leukemias, neuroblastomac and some carcinomas like breast and ovarian
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6
Q

what causes resistance to cyclophsphamide?

what are common adverse effects?

A
  • drug resistance occurs due to increase in DNA repair, decrease in drug permeability or reaction with other cellular constituents
  • adverse effects: mainly nausea and vomiting, also virtually all alkylating agents affect bone marroe causing immunosuppression and alopecia
  • can cause hemorrhagic cystitis, sterility menopause and veno-occusive disease of liver
  • treat adverse effects by discontinuation of drug, red blood cells and paltelt transfusion (maybe antibiotics if necessary)
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7
Q

what is Cisplatin

A

alkylating agent that is frequntly used- an inorganic metal

  • covalently bidns to N7 of guanine and interacts with cytosine and adenine
  • can kill cells in all stages of cell cycle and admin IV or locally
  • has major anti-tumour activity in genitourinary cancers like testicular, ovarian and bladder
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8
Q

toxicities and resistance to cisplatin

A
  • toxicities are nausea, vomiting, nephrotoxicity and neurotoxicity like paresthesia or hearing loss
  • resistance is due to increase in DNA repair, reactions with other cellular constituents or decrease in cellular uptake
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9
Q

what drug is very similar to cisplatin

A
  • carboplatin is v similar to cisplatin - both used to tret various cancers
  • both are coordinated complexes of platinum
  • the cis structure of the mol prives them with ability to cross link adjacent guanines on the same DNA strand (intrastrand cross-link) or much less frequently, on opporsite DNA strands (interstnad cross link)
  • similar compounds with transconformations cannot effectively cross link adjacent guanines
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10
Q
A
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11
Q

what are non covalent DNA binding agent

A

class of anticancer drugs

  • extracted from soil microbe Streptomyces that have anti tumour activity
  • mechansim of actions = forming tight drug-DNA interacts and free radical DNA damage
  • result = unwinding of DNA, impaired synthesis and strand breaks that interfere with cell proliferaiton
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12
Q

what is bleomycin

A
  • non covalent DNA Bidnign agents
  • froms a DNA-bleomycin-Fe(II) complex - oxidation of this compelx results in production of free radicals and DNA strand breakage cusing cells to stay in G2 phase
  • can be admin through variety of routes and used alone or in combo with other drugs to treat squamous cell carcinomas, lymphomas and testicular tumours
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13
Q

resistance and adverse effects from bleomycin

A

resistance due to increase in DNA repair, drug efflux and/or expression of antioxidant enzymes or bleomycin hydrolase

  • individuals taking bleomycin might experience pulmonary fibrosis, fever or anaphylaxis
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14
Q

what are antimetabolites

A

affect cell proliferation by interfereing with DNA and RNA synthesis by ihibiting availability of purines and pyrimadines

  • more effective in S phase of cycle cycle
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15
Q

what are the major classes of antimetbaolite anticancer drugs

A

folate antagonists (methotrexate), pyrimidine analoges (5-fluorouracil), purine analogs and sugar modifed analogs

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16
Q

how to methotrexate work

A

enters cell vai active transport and acts as a folic acid inhibitor

  • structurally simialr to folare and bidns to dihydrofolate (DHF) reductase
  • metabolite, methotrexate-polyglutamate is retained in cancer cells to further inhibt RNA/DNA synthesis
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17
Q

what is methotrexate usually used to treat?

A

use in combo with other drugs to treat some leukemias, lymphomas and carcinmoas such as head, neck, lungs, testes, breast and cervix

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18
Q

how is methotrexate administered and what are the adverse effects

A

administered intravenously or orally

  • adverse effects = myelosuppression, gastrointestinal distress, alopecia, teratogenic renal damage (at high doses) and liver damage (with long term treatment)
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19
Q

what contributes to resistance to methotrexate?

A
  • non proliferating cells increase DHF reductase expression (the thing methotrexate minds to)
  • decreasing bindign to DHF and decrease cellular uptake can contribute to resistance
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20
Q

what is fluorouracil

A
  • antimetabolite
  • enters cell via carrier mediated transport
  • converted to ribosul and deoxyribosul nucelotides metabolites
  • MOA is inhibition of thymidylate synthesis which decreases thymidine synthesis and ultimately DNA synthesis
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21
Q

what is fluorouracil used to treat?

A
  • primarily treats breast and GI carcinomas like colorectal, pancreatic and gastric
  • it is administered IV or topically for some skin cancers
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22
Q

adverse effects and resistance to fluorouracil

A
  • adverse effects = bone marrow depression, nausea, vomiting, diarrhea, oral and GI ulceration, anorexia and alopecia
  • resistance can occur when flurouracil metabolism increases, conversion to nucleotide metabolites decreses and/or thymidylate synthase activity increases
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23
Q
A
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24
Q

what drugs are inhiibtors of chromatin function

A
  • plant alkaloids or synthetic derivates of naturally occuring alkaloids
  • ex: topoisomerase inhibitors like topotecan or microtubule inhibitors like vincristine or paclitaxel
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25
Q

what is topotecan

A
  • anticaner topoisomerase inhibitor
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26
Q

what is vincristine

A
  • anti cancer microtubule inhibitor
27
Q

what is paclitaxel

A
  • anti cancer microtubule inhibitor
28
Q

how does topotecan work

A
  • modulates supercoiling y complexing with DNA and nicking one of the two strands
  • then enzyme assists with DNA replication and transcription
  • topotecan binds topoisomerase I DNA complex to prevent annealing of DNA breaks and targets cells in S phase of cell cycle
29
Q

how is topotecan administered and what types of cancers does it treat

A

admin via IV and treats metastatic ovarian cancer

30
Q
A
31
Q

what are adverse effects to topotecan and how deos resistacne develop

A

adverse effects: bone marrow suppression, nausea, vomiting, diarrhea, alopecia and headache.

resistance develops due to increase in transport of the drug out of cell and a decrease in expression or mutation in topoisomerase I

*topoisomerase II inhiibtors can also be sued to treat some tumours

32
Q

describe regualtion and supercoiling by type I topoisomerases

strand rotation model

A
  • type I topoisomerase binds to opposite stand of DNA double helix
  • topoisomerase then nickes one strand and remains bound to one of the nicked ends (filled green circle)
  • unbond end of nicked strand is able to unwind by one or more turns and then joined (religated) to its parent strand)
33
Q

describet he regulation of DNA strand supercoiling by type I topoisomerases

(strang passage model

A
  • type I topoisomerase binds to DNA double helix results in melting (separation) of 2 strands
  • DNA bound topoisomerase then introduces a nick into one strand, while remaining bound to each end of the broken DNA strand (filled green circles)
  • broken strand is passed through the helix and joined (religated) resuling in a net unwinding of DNA

*Camptothecins inhibit the joining of the broken strand of DNA after strand passage.

34
Q

what are microtubules

A

cylindrical hollow fibers composed of polymers of tubulin that polymerize to form mitotic spindles

  • not static structures, instead they possess inherent property called dynamic instability
35
Q

what is Vincristine

A

blocks tubulin polymerization which leads to dysfunctional spindle formation

36
Q

what is paclitaxel

A
  • promotes tubulin polymerization causing overly stbale microtubles can cell cannot divide

(inhibt chromatin fucntion - microtuble inhiibtor)

-kills cells in M stage of cell cycle

37
Q

what types of cancers does paclitaxel treat

A

good activity against advanced ovarian cancer, metastatic breast cancer and when combined with cisplatin it is used to treat non-small cell lung cancer

38
Q

adverse effects of paclitaxel and hwo would resistacne occur

A

may experience nausea, vomiting, hypersensitivity, alopecia, myelosuppression, peripheral neuropathy and pulomary toxicity

  • drug is metabolices by CYP 450 so hepatic function should be monitored
  • resistance may occur due to altered tubulin structure and efflux via P-glycoprotein in cell membrane
39
Q

what is vincrisitne

A
  • inhibitor of chromatic function, microtubule inhibtor
  • derived from periwinkle plant
  • kill cells in m stage of cell cycle
  • administed via IV in combo with other drugs
40
Q

what types of cancers does vincristine treat?

A
  • leukemias, lymphomas and other rapidly proliferating tumours.
41
Q

adverse effects of vincristine and resistance

A

nausea, vomiting, alopecia, myelosuppression and peripheral neuropathy

*drug interactions can also occur with anticonvulsants which accelerate metabolism and with antifungal agents which may slow down metabolism

  • resistance due to altered tubulin structure and efflux via p-glycoprotein in the cell membrane
42
Q

decribe the struture of the microtubule

A
  • microtubles are floow cylcindrical tubes that polymerize from tubulin subunits
  • each subunit is a deterdimer compoased of α-tubulin (shades of purple) and β-tubulin (shades of blue).

Both α-tubulin and β-tubulin bind GTP (dark shades of purple and blue)

  • β-tubulin hydrolyzes GTP to GDP after the tubulin subunit is added to the end of a microtubule (lighter shades of purple and blue).

*Microtubules are dynamic structures that grow and shrink lengthwise.

43
Q

how can steroid be used to treat cancer

A
  • some tumors are steroid senstiive so might be hormone responseive, dependent or both
  • in order for tumors to respond to treatment, they must have steroid receptors on their memrbanes

*regualte expresion of genes that are involves in cell growth and proliferation

44
Q

prednisone for caner treatment

A

* recall used to treat inflammatory disease

  • at higher conc can be effective in treating some cancers
  • this corticosteroid is converted to active form (presnisolone0 in liver and can idnuce apoptosis of leukemic and lymphoid cells
  • resistance may result following absence or mutation of steroid receptor
45
Q

adverse effects of presnisone

A

immunosuppression, hyperglycemia, ulcers, pancreatitis, weakening, osteoporosis, hypertension and mood changes.

46
Q

tamoxifen

A
  • steroid hormone that is partial agonsit of estrogen receptor
  • in estrogen sensitive tumour cells,it bidns to ER and prevents ER mediated gene expression which decreases tumor growth
  • currently used to treat and prevent estrogen dependent breast cancer
  • administered orally and metabolized in liver
47
Q

why must caution be taken with tamoxigen

A

some metabolites are ER agonists (espeically on endometrium) while others are antagonists

  • use with caution as it can induce uterine cancer (if this is a concern, aromatase inhibitors such as anastrozole can be used to treat breast cancer)
48
Q

resistance and adverse efects of tamoxifen

A

esistance develops it is usually due to absence or mutation of the receptor.

Adverse effects = hot flashes, nausea, vomiting, irregular periods, blood clots, cataracts and uterine cancer.

49
Q

what are the most immediate ways to reduce caner death rates

A

Prevention, screening and early detection

  • tretments may imporve survival but may not eradicate eery cancer cell - traditional chemo tends to kill healthy proliferative cells as well
50
Q

why is resistance in cancer cells complex

A
  • several different overlapping mechansims
  • tumours are heterogenous - treatemnt amy destroy one cell type iwthin the tuour but leave the resistant cell type to continue to divide
  • some cells acquire genetic defects that reduce sensitivity to cytotoxic agents such as reducing binding abiltiy of drug making treatment less effective
  • cna also exhibit decreased cell permeability which will impact the ability of drugs to enter and destroy the cells
51
Q

what is enhanced efflux

A

way cancer cells develop resistance

  • excrete the drug from cell through expression of transmemrbane proteins that enhance excretion
  • multidrug resistance is also possible via these efflux pumps that affect several drugs
52
Q

in what types of cancers is multidrug resistance common

A
  • ovarian, breast, prostate, gastrointestinal tract, lung, lymphoma and leukemia
  • several MDR proteins play a role in resistance including permeability glycoprotein (p-glycotrotein), MDR-associated protein, lung resistance protein and breast cancer resistance protein
53
Q

what is P glycoprotein

A

multi-drug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1)

  • transmembrane ATP bidning transporter and is expressed in intestinal epithelium, hepatocytes, renal tubules and capillary endothelial cells of BBB and Blood testes barriers
  • protects cells against toxins and inc expression in tumor cells interferes w/ chemotherapeutic agetns
54
Q

MOA of P glycoprotein

A
  • invovled stimulus binding of a drug and ATP molecule
  • following biding ATP hydrolysis shifts the position of the drug and phosphate release from ATP causes the drug to be excreated from the cell
55
Q

influece of tamoxifen and cisplatin on p glycoprotein

A

drugs like tamoxifen can reverse MDR in p-glycoprotein-expressing cells, while cisplatin has been shown to induce p-glycoprotein expression (although cisplatin itself does not bind to p-glycoprotein).

56
Q

what is the most common types of breast cancer

A

ductal (inside the milk duct, in situ or invasive) and lobular (inside milk-producing gland, in situ or invasive).

Other forms that are rarer include inflammatory breast cancer and male breast cancer.

57
Q

what is tumour grade

A

represents how closely cancer cells resemble thier normal precursors

  • ex: Grade 1 refers to organized cells that are not actively dividing, while Grade 3 refers to disorganized, irregular growth with many cells replicating.
58
Q

stage 0 of breast cancer

A

non invasive

59
Q

stage I of breast cancer

A
  • invasive tumours < 2cm, no lymph noe invovlement

treatment = surgery

60
Q

what is stage IIa and IIb for breast cancer

A

IIa: tumour <2cm, lymph nodes positive

IIb: >2cm, no lymph node invovlement

  • treatment: Surgery + radiation (no lymph node involvement)
  • 6 cycles of Cyclophosphamide, methotrexate and 5-fluorouracil
  • Tamoxifen (anastrozole)
  • HER-2 receptor antagonists (see below)
61
Q

stage IIIA, IIB and IIIC of breast cancer

A

IIIa; Lymph nodes positive, clumped together or stuck to other structures, tumour any size

IIIb: tumour any size, cancer spread to chest wall/skin, possible involvement of axillary lymph nodes or those near breast bone

IIIc: Cancer spread to chest wall/skin and lymph nodes at collar bone and breast bone, possible axillary lymph nodes

treatment:

  • Surgery + radiation (no lymph node involvement)

Chemotherapy combinations:

including doxorubicin, cyclophosphamide, paclitaxel and/or 5-fluorouracil

Tamoxifen (+/- anastrozole)

HER-2 receptor antagonists (see below)

62
Q

breast cancer stage IV

A

Cancer has spread to other organs (ie. lung, liver, bone, brain)

treatment

Surgery + radiation (no lymph node involvement)

Chemotherapy combinations:

including doxorubicin, cyclophosphamide, paclitaxel and/or 5-fluorouracil

Tamoxifen (+/- anastrozole)

HER-2 receptor antagonists (see below)

63
Q

what is herceptin

A
  • targeted therapy
  • monoclonal antibody that interferes with the HER-2 receptor called Trastuzumab or Herceptin
  • Herceptin binds to the HER-2 receptor and prevents binding of epidermal growth factor (EGF), which interferes with the cell cycle and decreases proliferation.
  • can use in combo with paclitaxel and is first line treatemtn for HER-2 overexpressing metastatic breast cancer
64
Q

what is Bevacizumab

A
  • targeted breast cancer therapy
  • angiogenesis inhibitor that targets the VEGF receptor 2.

It was approved by the FDA in 2008 for use in combination with paclitaxel for metastatic breast cancer.

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