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Pharmacology > Anticancer 2 > Flashcards

Anticancer 2 Flashcards

1
Q

PURINE ANALOGS?

A

6-MERCAPTOPURINE

6-THIOGUANINE

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2
Q

Describe 6 MERCAPTOPURINE (6-MP) and MOA

A

Thiol analog of hypoxanthine.
Converted to thio-IMP by the salvage pathway
enzyme, HGPRT.
• Thio-IMP inhibits the first step of the de novo
purine ring biosynthesis.
• Thio-IMP also blocks formation of AMP and
GMP from IMP.
• Also, dysfunctional RNA and DNA result form
incorporation of guanylate analogs.

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3
Q

Describe 6-mercaptopurine PK.

A 
Metabolized to thiouric acid
by xanthine oxidase.
If allopurinol is given to
reduce hyperuricemia,
dose of 6-MP must be
decreased to avoid
accumulation of the drug.
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4
Q

AE of 6-mercaptopurine?

A

Nausea, vomiting, diarrhea.
• Bone marrow suppression.
• Hepatotoxicity.

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5
Q

Describe 6-Thioguanine

A

Converted to the nucleotide, which then inhibits
purine synthesis and the phosphorylation of
GMP to GDP.
• It can be incorporated into RNA and DNA.

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6
Q

6-thioguanine use and difference from 6-mercaptopurine?

A

Used for acute nonlymphocytic leukemias.
• Allopurinol does not potentiate 6-TG action
because very little is metabolized to thiouric
acid.

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7
Q

AE for 6-thioguanine

A

Toxicities: same as for 6-MP
Nausea, vomiting, diarrhea.
• Bone marrow suppression.
• Hepatotoxicity.

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8
Q

Metabolism of Thiopurines

A

6-mercaptopurine and 6-thioguanine are also
metabolized by the enzyme thiopurine
methyltransferase (TPMT).
• Patients who have weak activity TPMT are at
increased risk for severe toxicities such as
myelosuppression.

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9
Q

What are the pyrimidine analogs?

A

5-Fluorouracil
Capecitabine
Cytarabine

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10
Q

Describe 5-FU?

A

Converted to the deoxyribonucleotide 5-FdUMP.
• 5-FdUMP inhibits thymidylate synthase: DNA
synthesis is inhibited.
•
‘Thymineless death’ results.
• 5-FU is also converted to 5-FUTP and
incorporated into RNA, interfering with RNA
processing and function.

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11
Q

5-Flurorouracil moa?

A

Thymidylate synthase
inhibition is the main
MOA of 5-FU.

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12
Q

5-FU Metabolism enzyme and consequent severe toxicitiy if enzyme low?

A

• 5-FU is mainly metabolized by the enzyme
dihydropyrimidine dehydrogenase (DPD).
• Deficiency of DPD is seen in up to 5% of cancer
patients.
• These patients may experience severe toxicity
such as myelosuppression, neurotoxicity and
life-threatening diarrhea.

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13
Q

How Leucovorin effect 5-FU?

A

The 5-FU/leucovorin combination is used as
chemotherapy for colorectal cancer.
• 5-FU inhibits thymidylate synthase by forming a
ternary complex involving the enzyme, the
substrate (5-FdUMP), and the cofactor (N5
, N10-
methylene-THF).
• Increasing levels of N5
, N10-methylene-THF
potentiates the activity of 5-fluorouracil.
• Therefore, leucovorin potentiates the activity
of 5-fluorouracil.

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14
Q

5-FU adverse effects?

A

Nausea, vomiting, alopecia, bone marrow
depression.
• An erythematous desquamation of the palms
and soles called the “hand-foot syndrome” is
seen after extended infusions.

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15
Q

Capecitabine descrube and AE?

A

Orally available prodrug of 5-FU.
• Capecitabine’s cytotoxic activity is the same as
that of 5-FU.
Nausea, vomiting, alopecia, bone marrow
depression.
• An erythematous desquamation of the palms
and soles called the “hand-foot syndrome” is
seen after extended infusions.

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16
Q

Cytarabine MOA?

A 
Analog of deoxycytidine.
• Sequentially phosphorylated
to the trisphosphate.
• Incorporated into DNA.
• The incorporated residue
inhibits DNA polymerase.
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17
Q

Description of antitumor antibiotics?

A

Bind to DNA through intercalation between bases
and block synthesis of new RNA or DNA, cause
DNA strand breakage, and interfere with cell
replication.

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18
Q

What two drugs are anthracyclines?

A

DOXORUBICIN
DAUNORUBICIN
The anthracycline antibiotics are among the
most important antitumor agents.
• Doxorubicin is one of the most widely used
anticancer drugs.

19
Q

Anthracycline MOA?

A 
Inhibition of topoisomerase II
• Intercalation in DNA with consequent
blockade of DNA & RNA synthesis and
strand breakage.
• Binding to cell membranes to alter fluidity
and ion transport.
• Generation of free radicals.
• The free radicals are the cause of the cardiac
toxicity.
20
Q

Anthracycline AE? Which agent can reduce one of the adverse effects?

A 
Myelosuppression.
• Cardiotoxicity:
• Dose-dependent, dilated cardiomyopathy
associated with heart failure.
• Due to free radicals.
• The iron-chelating agent dexrazoxane
can reduce the cardiotoxicity.
21
Q

Describe Bleomycin?

A

Mixture of glycopeptides.
• Like the antracyclines, bleomycin causes
breakage of DNA by oxidative processes.
• Cell-cycle specific. Arrest cells in G2 phase.

22
Q

Bleomycin MOA?

A 
A DNA-bleomycin-Fe2+
complex undergoes
oxidation to bleomycinFe3+
.
• The liberated electrons
react with O2
to form free
radicals which cause
strand breakage.
23
Q

Bleomycin AE?

A

Very little myelosuppression.
• The most serious adverse reaction is
pulmonary toxicity (pneumonitis, fibrosis).
• Dose-limiting.

24
Q

Describe Alkylating agents?

A

Exert cytotoxic effects via transfer of their alkyl
groups to various cellular constituents.
• Alkylation of DNA is probably what leads to
cell death.
• Alkylation of DNA can occur on a single DNA
strand or on both strands through cross-linking,
as most major alkylating agents are bifunctional.

25
Q

AE of alkylating agents, which one is most widely used?

A

Toxicities occur particularly in rapidly growing
tissues like the bone marrow, GI tract and
gonads.
• Nausea and vomiting are common.
• Alkylating agents are mutagenic and
carcinogenic.
• Cyclophosphamide is the most widely used
alkylating agent.

26
Q

What are the four subgroups of alkylating agents?

A 
Nitrogen mustards
Nitrosoureas
Other Alkylating Agents
Platinum Coordination
Complexes
27
Q

What are the 3 nitrogen mustrards?

A

Mechlorethamine
Cyclophosphamide
Melphalan

28
Q

Describe Mecholrethamine and AE?

A

Very unstable.
• Solutions must be made up just prior to
administration.
• Powerful vesicant. Only given IV.

Severe nausea and vomiting.
• Severe bone marrow depression.
• Alopecia.
• Immunosuppression.
• Largely replaced by cyclophosphamide,
melphalan and other more stable alkylating
agents.
29
Q

Describe cyclophosphamide?

A

Can be given orally or IV.
• Prodrug.
• Activated to 4-OH-cyclophosphamide by CYP2B.

Broad clinical spectrum.
• Essential component of many drug
combinations.
• Most widely used alkylating agent

30
Q

Cyclophosphamide AE?

A 
Nausea and vomiting
• Bone marrow depression
• Hemorrhagic cystitis
• Alopecia
• Sterility
31
Q

How can cyclophosphamide AE be diminished?

A

Acrolein, a metabolite of cyclophosphamide is
responsible for the hemorrhagic cystitis.
• This can be prevented by adequate fluid intake
and parenteral administration of mesna, a sulfhydryl
compound which reacts with acrolein in the bladder.

32
Q

Adverse effect of melphalan

A

Bone marrow suppression

33
Q

What are the Nitrosoureas?

A

CARMUSTINE & LOMUSTINE

34
Q

Describe Nitrosoureas

A

Very lipophilic.
• Cross the blood-brain barrier.
• Useful in treatment of brain tumours.

35
Q

What are the other 3 alkulating agents?

A

BUSULFAN
• DACARBAZINE
• PROCARBAZINE

36
Q

Busulfan AE?

A

Myelosuppression is the main toxicity.

• May cause pulmonary fibrosis.

37
Q

Describe Dacarbazine and AE?

A

Acts as methylating agent after activation in the
liver.
• Given IV.
• Toxicity includes nausea and vomiting.
• Myelosuppression is usually mild to moderate.

38
Q

Describe procarbazine and AE?

A 
Converted by liver P450 enzymes to alkylating
metabolites.
ADVERSE EFFECTS
• Bone marrow depression.
• Nausea and vomiting.
• Weak MAO inhibitor: hypertensive reactions
may result if given with sympathomimetic
agents, or tyramine-containing foods.
• Disulfiram-like reactions.
• Mutagenic and teratogenic
39
Q

What are the platinum coordination complexes?

A

CISPLATIN

CARBOPLATIN

40
Q

Describe platinum coordination complex activity?

A

Do not alkylate DNA. But covalently bind to DNA
and share many pharmacological properties with the alkylating agents.
• Broad antineoplastic activity.
• Have become the foundation for treatment of
testicular cancer, ovarian cancer, and cancers of
the head and neck, bladder, esophagus, lung
and colon.

41
Q

Cisplatin and carboplatin MOA?

A

Inhibit DNA synthesis and bind DNA through
formation of cross-links.
• Given IV.

42
Q

Cisplatin AE? Which agent is used to reduce one of the adverse effect?

A 
Myelosuppression: mild-to-moderate.
• Nausea and vomiting.
• Ototoxicity.
• Peripheral neuropathy.
• Nephrotoxicity is reduced by hydration
and diuresis.
• Amifostine is a cytoprotective agent
used to reduce the renal toxicity
associated with cisplatin.
43
Q

Carboplatin AE?

A

Less nausea, neurotoxicity, ototoxicity and
nephrotoxicity than cisplatin.
• Dose-limiting toxicity is myelosuppression.

Pharmacology (49 decks)

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