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Block 5 Pharmacology > Cancer Chemotherapy- DNA Synthesis Inhibitors > Flashcards

Cancer Chemotherapy- DNA Synthesis Inhibitors Flashcards

1
Q

Why are Chemo agents given in combination (3)

A
  • Produce synergistic activity
  • Prevent drug resistance
  • Decrease toxicity
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2
Q

What are the 2 Combination Chemotherapies used for Lung Cancer

A
  • CAV
    • C = Cyclophosphamide
    • A = Adriamycin (doxorubicin)
    • V = Vincrisitine
  • CAE
    • C = Cyclophosphamide
    • A = Adriamycin
    • E = Etoposide
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3
Q

What are the 2 Combination Chemotherapies used for Breast Cancer

A
  • CMF
    • C = Cyclophosphamide
    • M = Methotrexate
    • F = 5-Fluorouracil (5-FU)
  • AC
    • A = Adriamycin
    • C = Cyclophosphamide
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4
Q

What are the 2 Combination Chemotherapies used for Colon Cancer

A
  • FolFOx
    • Fol = Folinic Acid (Leucovorin)
    • F = 5-FU
    • OX = Oxaliplatin
  • FOLFIRI
    • Fol = Folinic Acid (Leucovorin)
    • F = 5-FU
    • Iri = Irinotecan
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5
Q

What are the 2 Combination Chemotherapies used for Leukemias

A

Anakin Becomes Darth Vader, then CHOPS off Luke’s hand

  • ABDV
    • A = Adriamycin
    • B = Bleomycin
    • V = Vinblastine
    • D = Darcarbazine
  • CHOP-R
    • C = Cyclophosphamide
    • H = Hydroxydaunorubicin (doxorubicin)
    • O = Oncovin (ie Vincristine)
    • P = Prednisone
    • R = Rituximab
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6
Q

For which Leukemias would you use the ABVD treatment combo

A

Hodgkins Lymphoma

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7
Q

For which Leukemias would you use the CHOP-R treatment combo

A

Non-Hodgkins Lymphoma

CLL

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8
Q

What are 4 classes of DNA Synthesis Inhibitors and examples of each

A
  • Folate Antagonists: (Methotrexate)
  • Purine Antagonists: (6-mercaptopurine , 6-thioguanine)
  • Pyrimidine Antagonists: (5-Fluorouracil)
  • Ribonucleotide Reductase Inhibitors: (Gemcitabine)
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9
Q

What is the Mechanism by which Methotrexate works and how does it show selective toxicity?

A
  • DHFR converts folic acid to FH2(DHF) and FH4(THF)
  • The THF is required for DNA and RNA synthesis (donates carbon group for purine synthesis)
  • MTX binds to and inhibits DHFR to block synthesis of FH4 thus blocking DNA and RNA synthesis

-MTX is more selective for the Eukaryote DHFR than prokaryote DHFR (trimethoprim selective for pro dhfr) and accumulates in rapidly dividing cells since they require high levels of folate and nucleotide precursors

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10
Q

How is MTX taken into the cell and how is it processed once in the cell

A
  • MTX enters the cell through the folate receptor or reduced folate transporter
  • once inside it is polyglutamated by: Folypolyglutamate synthase
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11
Q

What is the significance of glutamated MTX

A
  • Polyglutamated MTX is more active than MTX
  • MTX inhibits DHFR
  • Polyglutamated MTX also binds and inhibits TS (thymidylate synthase) which creates dTMP from dUMP and is needed to create dTTP and form DNA
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12
Q

How is Methotrexate:

  • Administered
  • Absorbed/Distributed (CNS?)
  • Eliminated
A
  • Oral or Parenteral
  • Well absorbed and distributed
    • No CNS penetration; intrathecal admin for ALL
  • Renal Excretion
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13
Q

In which combination therapy and for which Cancer is Methotrexate used and what are its 2 non cancer uses

A
  • CMF (cyclophosphamide, MTX, 5-FU)
  • For Breast Cancer

NON Cancer Uses

  • Rheumatoid arthritis
  • Psoriasis
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14
Q

What are 5 adverse effects seen with Methotrexate and which is the primary one?

A
  • Bone Marrow Suppression (primary dose limiting tox)
  • GI toxicity
  • Stomatitis
  • Kidney damage
  • Hepatotoxicity
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15
Q

What treatment is used to try to prevent adverse effects of Methotrexate and how does it work?

A
  • Leucovorin (folinic acid) “Leucovorin Rescue”
  • Can PREVENT but not reverse adverse effects
  • Can donate a carbon group without being reduced by DHFR; this allows low level of DNA synthesis. The low level is enough to sustain and rescue normal cells but not the tumor cells who have a higher demand
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16
Q

What are the 3 mechanisms of resistance against Methotrexate

A
  • Decreased Drug activation (Folypolyglutamate synthase down regulation)
  • Increased target expression: more DHFR then can be inhibited
  • Decreased drug accumulation: mutation and decreased expression of the two transporters (folate receptor and reduced folate transporter)
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17
Q

What is the class and mechanism of action of 6-mercaptopurine and 6-thioguanine

A
  • Purine antagonists
  • 6-MP and 6-TG are converted to Thio-dGTP by HPRT
  • Thio-dGTP is incorporated into the growing DNA chain and inhibits the DNA polymerase terminating the chain

-MeTIMP (methyl thioinosine monophosphate) a metabolite of 6-MP also inhibits de novo purine biosynthesis

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18
Q

How is 6-Mercaptopurine:

  • Administered
  • Absorbed/Distributed (CNS?)
  • Metabolized
  • Eliminated
A
  • Oral
  • Absorption: Decreased by Food
  • Well Distributed
  • Does not cross BBB
  • Inactivated by Thiopurine methyl transferase (TPMT) AND Xanthine Oxidase (XO)
  • Renal Excretion
19
Q

How is 6-Thioguanine:

  • Administered
  • Absorbed/Distributed (CNS?)
  • Metabolized
  • Eliminated
A
  • Oral
  • Absorption: Decreased by Food
  • Well Distributed
  • Does not cross BBB
  • Inactivated ONLY BY TPMT (whereas 6-MP inactivated by TPMT AND XO)
  • Renal Excretion
20
Q

What are the Non-Cancer uses of 6-MP and 6-TG

A
  • IBD (inflammatory bowel disease)

- Immunosuppressant

21
Q

2 adverse effects of 6-MP and 6-TG and which is dose limiting and what can alter the toxicities

A
  • Bone marrow suppression (dose limiting)
  • Hepatotoxicity
    Both can be affected by the TMPT levels of the patient in which some patients are deficient/have low activity
22
Q

In what scenarios does the differing metabolisms of the purine antagonists come into play and which antagonist would then be favored?

A
  • Variant type TMPT gene causing dec gene activity and dec drug inactivation: 6-MP would be favored due to additional degradation pathway by XO
  • Those patients with gout on Allopurinol; it inhibits the XO enzyme and thus would cause accumulation and inc toxicity of 6-MP: thus 6-TG would be favored or 6-MP dose reduced
23
Q

What is the Pathophysiology behind the Varient TMPT type effect on purine antagonists

A
  • 25% of the population has an altered TMPT gene which decreases its activity (v/wt)
  • and a smaller percentage have even less function (v/v type) they have severe hematopoieteic and hepatic toxicity requiring 90% dose reduction
24
Q

What are 2 mechanisms of resistance to Purine antagonists

A
  • Decreased Drug Activation: Low HPRT dec activation

- Inc Drug inactivation: High TPMT inc inactivation

25
Q

What is the mechanism of Pyrimidine antagonists

A
  • 5-FU analogue of uracil which is converted to multiple products to have multiple effects

Uracil has been observed to be utilized more rapidly by tumor cells than normal cells

26
Q

What are the 3 products which 5-FU is transformed into

A
  • 5-FdUMP
  • 5-FdUTP
  • 5-FUTP
27
Q

What is the mechanism of action of the 5-FdUMP product of 5-FU

A
  • Binds thymidylate synthase (TS) thus inhibiting dTTP synthesis (causing DNA damage)
28
Q

What is the mechanism of action of the 5-FdUTP product of 5-FU

A
  • Is incorporated into DNA; then continuous repair attempts cause DNA damage
29
Q

What is the mechanism of action of the 5-FUTP product of 5-FU

A
  • Is incorporated into RNA; thus inhibiting RNA synthesis
30
Q

How is 5-Fluorouracil:

  • Administered
  • Absorbed/Distributed (CNS?)
  • Metabolized
  • Eliminated
A
  • Parenteral or Topical (NO ORAL)
  • Well Distributed and CROSSES BBB
  • No absorption info because not taken orally
  • DPD (dihydropyrimidine dehydrogenase) inactivates 5-FU
  • HEPATIC excretion (some renal)
31
Q

In which combination therapies and for which Cancers is 5-FU used and what are its non cancer uses

A
  • Colorectal Cancer
    • FolFOx (Leucovorin, 5-FU, Oxaliplatin)
    • FOLFIRI (Leucovorin, 5-FU, Irinotecan)
  • Breast Cancer
    • CMF (Cyclophosphamide, MTX, 5-FU)
      NON Cancer Uses
  • Actinic keratosis
32
Q

What are 4 adverse effects of pyrimidine antagonist use and which is dose limiting

A
  • Myleosuppression (dose-limiting)
  • Oral and GI ulceration
  • Neurotoxicity
  • Inflammation, Irritation (topical)
33
Q

What is the effect of giving Leucovorin (folinic acid) with a pyrimidine antagonist

A

Leucovorin (CH2THF) binds to Thymidylate synthetase Which increases its affinity for FdUMP and thus causes greater inhibition of TS

34
Q

Compare the purposes of giving Leucovorin (folinic acid) with 5-FU and with Methotrexate

A
  • Given with 5-FU: Increases binding affinity to TS and thus efficacy is increased
  • Given with Methotrexate: Provides carbon groups for normal cells to reduce adverse effects
35
Q

What are 2 mechanisms of resistance against 5-FU

A
  • Increased drug target expression: Promoter mutation increases TS expression thus allowing restoration of DNA synthesis
  • Increased Drug inactivation: increased levels of DPD which increases inactivation of 5-FU to DHFU
36
Q

What is the chemical name and general mechanism of action of Gemcitabine

A
  • Difluorodeoxycytidine (dFdC)

- Several MOA but maostly Ribonucleotide reductase inhibition

37
Q

How does Gemcitabine enter the cell

A

Taken into cell by:
- ENT (equilibrative nucleoside transporter)
- CNT (concentrative nucleoside transporter)
CNT is an active transporter and thus is responsible for most of the transport of gemcitabine

38
Q

What are are the active forms of Gemcitabine when its in the cell

A
  • dFdCDP
  • dFdCTP

(dFdC can be inactivated to dFdU by cytidine deaminase)
(dFdCMP can be inactivated to dFdUMP by dCMP deaminase)

39
Q

What is the mechanism of the dFdCDP form of Gemcitabine

A
  • inhibits ribonucleotide reductase

- which causes base depletion and thus inhibits DNA synthesis

40
Q

What is the mechanism of the dFdCTP form of Gemcitabine

A
  • Competes with dCTP and incorporates into the DNA causing chain termination
  • Also inhibits cytidine deaminase which INHIBITS THE BREAKDOWN OF THE dFdC (GEMCITABINE)
41
Q

How is Gemcitabine:

  • Administered
  • Absorbed/Distributed (CNS?)
  • Metabolized
  • Eliminated
A
  • Parenteral
  • Distribution not well characterized (absorption not noted because not orally taken)
  • Will Cross BBB at low levels
  • Deaminated (by cytidine and dFdCMP deaminases) to inactive uracil metabolites)
  • Renal excretion
42
Q

What is the common Cancer Gemcitabine is used for

A

Pancreatic Cancer

43
Q

What are 3 adverse effects with Gemcitabine

A
  • Myelosuppression
  • GI toxicity
  • CNS effects
44
Q

What are 2 mechanisms of resistance to Gemcitabine

A
  • Increased Drug Inactivation: high cytidine deaminase

- Decreased drug accumulation: dec influx via CNT

Block 5 Pharmacology (8 decks)

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