Anticancer 2 Flashcards
PURINE ANALOGS?
6-MERCAPTOPURINE
6-THIOGUANINE
Describe 6 MERCAPTOPURINE (6-MP) and MOA
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.
Describe 6-mercaptopurine PK.
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.
AE of 6-mercaptopurine?
Nausea, vomiting, diarrhea.
• Bone marrow suppression.
• Hepatotoxicity.
Describe 6-Thioguanine
Converted to the nucleotide, which then inhibits
purine synthesis and the phosphorylation of
GMP to GDP.
• It can be incorporated into RNA and DNA.
6-thioguanine use and difference from 6-mercaptopurine?
Used for acute nonlymphocytic leukemias.
• Allopurinol does not potentiate 6-TG action
because very little is metabolized to thiouric
acid.
AE for 6-thioguanine
Toxicities: same as for 6-MP
Nausea, vomiting, diarrhea.
• Bone marrow suppression.
• Hepatotoxicity.
Metabolism of Thiopurines
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.
What are the pyrimidine analogs?
5-Fluorouracil
Capecitabine
Cytarabine
Describe 5-FU?
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.
5-Flurorouracil moa?
Thymidylate synthase
inhibition is the main
MOA of 5-FU.
5-FU Metabolism enzyme and consequent severe toxicitiy if enzyme low?
• 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.
How Leucovorin effect 5-FU?
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.
5-FU adverse effects?
Nausea, vomiting, alopecia, bone marrow
depression.
• An erythematous desquamation of the palms
and soles called the “hand-foot syndrome” is
seen after extended infusions.
Capecitabine descrube and AE?
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.
Cytarabine MOA?
Analog of deoxycytidine. • Sequentially phosphorylated to the trisphosphate. • Incorporated into DNA. • The incorporated residue inhibits DNA polymerase.
Description of antitumor antibiotics?
Bind to DNA through intercalation between bases
and block synthesis of new RNA or DNA, cause
DNA strand breakage, and interfere with cell
replication.
What two drugs are anthracyclines?
DOXORUBICIN
DAUNORUBICIN
The anthracycline antibiotics are among the
most important antitumor agents.
• Doxorubicin is one of the most widely used
anticancer drugs.
Anthracycline MOA?
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.
Anthracycline AE? Which agent can reduce one of the adverse effects?
Myelosuppression. • Cardiotoxicity: • Dose-dependent, dilated cardiomyopathy associated with heart failure. • Due to free radicals. • The iron-chelating agent dexrazoxane can reduce the cardiotoxicity.
Describe Bleomycin?
Mixture of glycopeptides.
• Like the antracyclines, bleomycin causes
breakage of DNA by oxidative processes.
• Cell-cycle specific. Arrest cells in G2 phase.
Bleomycin MOA?
A DNA-bleomycin-Fe2+ complex undergoes oxidation to bleomycinFe3+ . • The liberated electrons react with O2 to form free radicals which cause strand breakage.
Bleomycin AE?
Very little myelosuppression.
• The most serious adverse reaction is
pulmonary toxicity (pneumonitis, fibrosis).
• Dose-limiting.
Describe Alkylating agents?
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.
AE of alkylating agents, which one is most widely used?
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.
What are the four subgroups of alkylating agents?
Nitrogen mustards Nitrosoureas Other Alkylating Agents Platinum Coordination Complexes
What are the 3 nitrogen mustrards?
Mechlorethamine
Cyclophosphamide
Melphalan
Describe Mecholrethamine and AE?
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.
Describe cyclophosphamide?
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
Cyclophosphamide AE?
Nausea and vomiting • Bone marrow depression • Hemorrhagic cystitis • Alopecia • Sterility
How can cyclophosphamide AE be diminished?
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.
Adverse effect of melphalan
Bone marrow suppression
What are the Nitrosoureas?
CARMUSTINE & LOMUSTINE
Describe Nitrosoureas
Very lipophilic.
• Cross the blood-brain barrier.
• Useful in treatment of brain tumours.
What are the other 3 alkulating agents?
BUSULFAN
• DACARBAZINE
• PROCARBAZINE
Busulfan AE?
Myelosuppression is the main toxicity.
• May cause pulmonary fibrosis.
Describe Dacarbazine and AE?
Acts as methylating agent after activation in the
liver.
• Given IV.
• Toxicity includes nausea and vomiting.
• Myelosuppression is usually mild to moderate.
Describe procarbazine and AE?
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
What are the platinum coordination complexes?
CISPLATIN
CARBOPLATIN
Describe platinum coordination complex activity?
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.
Cisplatin and carboplatin MOA?
Inhibit DNA synthesis and bind DNA through
formation of cross-links.
• Given IV.
Cisplatin AE? Which agent is used to reduce one of the adverse effect?
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.
Carboplatin AE?
Less nausea, neurotoxicity, ototoxicity and
nephrotoxicity than cisplatin.
• Dose-limiting toxicity is myelosuppression.
