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MO2 > DNA alkylating and platinating agents > Flashcards

DNA alkylating and platinating agents Flashcards

1
Q

define chemotherapy

A

he controlled use of chemicals for a medicinal purpose

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2
Q

define cancer chemotherapy

A

use of cytotoxic medications and chemicals to effect a cure in some cancers (leukaemia’s, lymphomas, some solid tumours), to decrease tumour size, or to serve as an adjuvant to surgery or radiation (prevent or treat metastasis)

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3
Q

when does cancer chemotherapy work best?

A

Works best in low disease burden as found in early stages of cancer
– toxicity from difference in growth rate of cancer vs. normal cells
– reduced capacity of cancer vs. normal cells to repair DNA lesions, triggering
apoptosis

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4
Q

what is combination chemotherapy

A

Treatment with combinations of several anticancer agents
– mechanisms of action complement each other to produce maximal cell kill
* Decreases the possibility of development of resistance to individual cytotoxic agents
– offers broader range of coverage of new resistant tumour cell lines and can prevent or slow development of
new resistant cell lines

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5
Q

what are the components of combination chemotherapy?

A

must be active as single agents
have different mechanisms of action and/or targets have minimal overlapping toxicity
combined in maximum dose and optimal schedule (determined experimentally)
increases cytotoxicity without necessarily increasing the general toxicity

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6
Q

what is the benefit of giving in intermediate doses?

A

permits recovery of normal tissues (e.g.bone marrow regeneration)
between treatment cycles.

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7
Q

what would be the size o 1) clinical detectable tumours and lethal tumours?

A

Clinical detectable tumour: ~10>9 cells (1 cm, ~1 g)
* Lethal tumours: ~10>12 cells

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8
Q

what are the doubling times for cancer cells for Hodgkins disease and testicular teratoma?

A

3-6 days

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9
Q

what are the doubling times for breast, prostate, lung and colon cancers?

A

80-100 days

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10
Q

how long can re-emergency occur for?

A

10 -15 years after remission achieved

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11
Q

what is the fractional cell kill hypothesis?

A

each time the chemotherapy dose is repeated, the same proportion of cells,
not the same absolute number, is killed … (99%kill per cycle: 1011*0.016 < 1)

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12
Q

what is the 3 log kill,1 log regrowth principle?

A

– in a tumour with 1011 cells, a cycle of chemotherapy treatment will result in
103 (3 log kill) cells dying and 108 cells remaining
– repeated cycles are required to eradicate remaining and re-growing cells
– 1011 -> 108 -> 109 -> 106 -> 107 -> 104 -> 105 -> 102 -> 103 -> .

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13
Q

what cellular proliferation is rapid / slow?

A

rapid: bone marrow, GI mucosa, Ovary, Testis, Hair folicles
slow: liver, lung, kidneys, endocrine glands, vascular endothelium

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14
Q

what are some of the proliferative side effects?

A

Myelosuppression, immunosuppression, mucositis, GI disturbances, alopecia,
gonadal damage
– relative sensitivities exist
– some low proliferative tissues can exhibit increased sensitivity

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15
Q

what are some non-proliferative toxicities?

A
  • not necessarily the same mechanism as anticancer activity
  • may be due to effects on cell components other than DNA
  • commonly limited to one drug, or group of drugs
    – may be avoidable by use of analogues
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16
Q

what are alkylating agents? what are their chemical properties?

A

Highly reactive, electrophilic compounds –form covalent bonds (SN1 and SN2
mechanisms)
– oxygen in phosphate groups of RNA/DNA
– oxygen of purines and pyrimidines
– amino groups of purines
– primary and secondary amino groups of proteins
– sulfur of methionine
– thiolof cysteine (protein and glutat

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17
Q

how do alkylating agents cross link DNA?

A

miscoding through abnormal base-pairing with thymine (T-G rather than C-G)
– depurinationby excision of guanine residues, leading to strand breakage

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18
Q

how many hydrogen bonds are there in A-T, C-G?

A

A-T= 2 hydrogen bonds
C-G= 3 hydrogen bonds

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19
Q

what are the different types of alkylating agents?

A

nitrogen mustards
nitrosoureas
platinum compounds
others: busulfan,treosulfan, thiotepa, temozolamide, dacarbazine, procarbazine

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20
Q

what are the properties of the alkylating agents?

A
  • non-cell cycle specific
  • most effective
    against cells in the G1
    or M phase
  • also impair
    progression from the
    G1 and S phases to
    the M phase
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21
Q

what are nitrogen mustards?

A

Major class of alkylating agents used in antineoplastic chemotherapy are nitrogen
mustards

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22
Q

what was nitrogen mustards based off of ?

A

Bis(2-chloroethyl)sulfide
– chemical warfare agent
– toxic
– extensively used in World Wars I and II

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23
Q

how did Bis(2-chloroethyl)sulfide change to mustine?

A

Replacement of sulfurby N-CH3

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24
Q

what was mustine used to treat?

A

– treatment of lymphomas
– Hodgkin’s disease

25
Q

what are the properties of mustine?

A
  • Nitrogenous
  • Basic
  • Administered as hydrochloride salt
    – stable solid
  • Less toxic than sulfurmustard
  • Rapidly inactivated
26
Q

how does the chemical properties of mustards change?

A

the R group attached to the N

27
Q

what is the MOA of nitrogen mustards?

A
  • Alkylating agents form covalent bonds to cell substituents
  • Alkylating agents are electrophilic species
    – React with nucleophilic group on DNA
    – Main molecular target is N-7 of guanine
    – N-1, N-3 of adenine and N-3 of cytosine also effected
28
Q

how are most cytotoxic anticancer alkylating agents bifunctional?

A

intra-chain linking
– inter-chain cross linking

29
Q

how are Nitrogen mustards cell cycle nonspecific?

A

– can interact with DNA of resting and proliferating cells
– more toxic to growing cells
* main cytotoxic action occurs during replication phase of cell cycle
* base pairs not hydrogen-bonded
* more susceptible to alkylation
– dormant cells can repair alkylation damage
– proliferation dependent … dependent on growth-fraction of tumor

30
Q

what are nitrogen mustards toxic mechanism?

A

– DNA strands are cross-linked and cannot unwind, structure distorted
– interferes with transcription, replication, replication enzymes
– inhibits cell division
– excision of the guanine base with main chain scission
– pairing of alkylated guanine with thymine instead of cytosine
– base pair substitution of GC with AT
– ineffective repair … frameshiftmutation

31
Q

what signalling pathways does Nitrogen mustards introduce?

A
  • Crosslinks induces p53 and DNA damage-induced apoptotic pathways
  • Converge on caspase by release of cytochrome c from mitochondrial inter-membrane
    space to cytosol
  • Mitochondrial apoptotic pathway activation and apoptosis
  • ERK, PI3K/AKT/PTEN and Death pathways
  • Activation of pathways leads to upregulation of proapoptoticgenes (TRAIL) and tumor
    suppressor genes (PTEN)
32
Q

what is mustines structural mode of action?

A

– nitrogen lone pair
– electron rich
– nucleophilic
– electronegative chlorine
– internal nucleophilic substitution
– SN1-like fast unimolecularreaction to aziridiniumcation
– rapid reaction

33
Q

what is the role of aziridinium cations in mustine MOA?

A

3 membered nitrogen containing ring
– relatively stable in aqueous biological fluids
– ring strain -> reactive towards nucleophiles
– SN2-like …. rate-controlling bimolecular

34
Q

why is N-7 of guanine the main nucleophile?

A

it is the most exposed in the DNA helix

35
Q

what is chlorambucil?

A

One of slowest acting, best distributed, least toxic nitrogen mustards
* Less basic than mustine
* Less reactive than mustine
less toxic

36
Q

why are aromatic amines considerably weaker bases than aliphatic amines?

A

Nitrogen lone pair of aromatic amines is less nucleophilic than that of aliphatic
amine
* Resonance!!

37
Q

what is melphalan?

A
  • Nitrogen mustard derivative of L-phenylalanine
38
Q

what is the result of phenalanine being ionised at all physiological PHs?

A

– cannot partition by passive diffusion
– absorbed by active transport
– stereospecific transport mechanism
– D-enantiomer absorbed at ~1% level of L-enantiomer
– plasma levels of melphalantend to be higher than conventional mustards

39
Q

what is cyclophosphamide?

A

Most commonly used alkylating agent, most often used in combination with other
antineoplastics

40
Q

why is cyclophosphamide inactive until the liver?

A

metabolised by the liver
– a pro-drug
– activated by cytochrome P450 and is 80-90% metabolised in liver
– active agent is normustine… bifunctionalalkylating agent

41
Q

what is the purpose of phosphoramidase? wh at does it do?

A

cleabes P-N bonds
reduced nucleophilicityof nitrogen lone pair due to resonance

42
Q

what problems are associated with acrolein metabolite?

A

– irreversible alkylation of cysteine residues
– potential for significant renal and bladder damage
– haemorrhagic cytisis

43
Q

how do you ameliorate acrolein?

A

– increasing fluid intake
– administer sulfhydryl donors at 0, 4, 8 h of treatment
* act specifically with acrolein
* form non-toxic compounds
* excreted more rapidly than cyclophosphamide and metabolites

44
Q

what ways does resistance occur?

A
  • decreased prodrug activation by key enzymes, CYP3A4 and CYP2B6
  • increased metabolism (deactivation)
  • decreased entry into tumorcells
  • increased efflux from tumorcells
  • increased cellular thiol levels
    – elevated levels of glutathione detoxification of electrophilic species
  • increased DNA repair capacity
  • deficient apoptotic response to DNA damage
45
Q

what is estramustine?

A

capsules containing estramustinephosphate 140 mg (disodium salt monohydrate)

46
Q

what is the benefit of combining estradiol and nitrogen mustards?

A

– carbamatefunctionallity… lowers nitrogen nucleophilicity
– phosphate … increases water solubility
– estradiol –efficiently crosses biological membranes
– targets cells with estrogenic receptors
– may alkylate as intact drug or cleavage by plasma or carbamaseenzymes (pro-drug)

47
Q

what is thiotepa?

A

– example of an aziridine
* Chemically less reactive than nitrogen mustards, thought to act by a similar
mechanism
most commonly used in bladder cancer

48
Q

when would you use alkyl sulfonates because of their selective effect in bone marrow?

A

– chronic myelogenousleukaemia
– little effect on lymphoid tissue, GI tract

49
Q

how does bifunctional alkylating agent work?

A

– SN2 mechanism
– sulfonategroups are better leaving group than
chloride in nitrogen mustards
– reacts with thiolgroups of amino acids
– cytotoxic effect may not be through alkylation
of DNA ??

50
Q

what are chloroethylnitrosoureas?

A

ifunctional, derivatives of urea
* cross-link DNA (N-7, O-6 of
guanine, N-3 of cytosine)
– lipid soluble, cross blood-brain
barrier
– pro-drugs
– non-selective, highly reactive -
very toxic agents

51
Q

when are nitrosoureas used?

A

Tumoursof CNS, Hodgkin’s disease,
lung cancer

52
Q

what is streptozotocin?

A

Streptozotocinis a glucosamine-nitrosoureadistributed as Zanosar

53
Q

how does streptozotocin work?

A
  • Mechanisms of action not clear
    – proposed to be related to the generation of free radicals
    – formation of methyl diazoniumion CH3N2+
    – carbamoylation of proteins
54
Q

how do temozolomide/ dacarbazine work?

A
  • Both prodrugs
  • Both implicated as alkylating agents
    – DNA methylation
    – guanine bases, O6 (main cytotoxic), N7 (major site, less toxic)
    – reduced activity of O6-alkylguanine-DNA-alkyltransferase (ATase)
55
Q

what is cisplatin?

A
  • Cis-diaminedichloroplatinum (II)
  • Water-soluble planar coordination complex
  • Similar action to alkylating agents
    – platinating(metalating) agent
    – cross-links DNA
    – N-7 guanine, N-7 adenine involved
  • Slow intravenous injection / infusion
56
Q

what does cisplatin contain? what position?

A

Contains a Pt central atom surrounded by 2 Cl and 2 NH3 in the cisposition
* Tetra-coordinate transition metal with square planar geometry

57
Q

what is Cisplatins MOA?

A

Cisplatin binds to DNA, behaving as a bifunctionalalkylating agent
* Intrastrandplatinationpredominates (cis-geometry of functionality)
* N-7 of guanine in major groove is the favouredsite!!
– binds preferentially at N-7 of purines (A,G) and N-3 of pyrimidines (C,T)
– two bases are not usually more than one base apart
* primarily crosslinks DNA on a single strand
* -G-G-(60-65%) , -A-G-(25-30%), -G-X-G-(5-10%), -G-X-A-/ inter-G-G-(1-3%)
– interaction with other nucleophiles is also possible
Cisplatin alters the physical structure of DNA when it is bound to it, but the overall
structure remains intact
* Unwinding at complexationsite alters DNA structure prevents replication

58
Q

why are liposomal products good?

A
  • Liposomes have ability to target cancer cells
  • The endothelial wall of all healthy human blood vessels are encapsulated by
    endothelial cells that are bound together by tight junctions
    – stop any large particle in the blood from leaking out
59
Q

how does lipoplatin work?

A

Reverse micelle between cisplatin and dipalmitoylphosphatidylglycerol (DPPG) converted
into liposomes by interaction with polyethylene glycol (PEG)
– protects liposomes from detection by mononuclear phagocytes
* Minimises toxic exposure to normal tissues while maximising tumour uptake and penetration
of the drug
* Negatively-charged DPPG molecule on the surface gives nanoparticles fusogenicproperties
(important feature for cell entry across the nuclear membrane barrier)
* Small size results in passive extravasation to tumours -more avid phagocytosis characteristic
of tumour cells further enhances the intracellular and nuclear uptake of the drug
* PEG coating gives particles prolonged circulation times as a nanoparticle in body fluids
(essential for tumour accumulation)
* Targets primary tumours and metastases causing greater damage to tumour tissue compared
to normal tissue

MO2 (55 decks)

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