Anticancers Flashcards
1
Q
Cell cycle specific agents
A
- antimetabolites
- bleomycin
- microtubule inhibitors
- epipodophyllotoxins
- camptothecins
2
Q
cell cycle nonspecific agents
A
- alkylating agents
- platinum coordination complexes
- antitumour antibiotics
3
Q
MULTIDRUG RESISTANCE
A
- Mainly due to overexpression of membrane efflux pumps; P-glycoprotein is the most important efflux pump responsible for multidrug resistance.
4
Q
TOXICITY: COMMON ADVERSE EFFECTS
A
- Doxorubicin causes cardiotoxicity.
- Cyclophosphamide & ifosphamide cause hemorrhagic cystitis.
- Bleomycin causes pulmonary fibrosis.
5
Q
MINIMIZING ADVERSE EFFECTS
A
- Leucovorin rescues bone marrow from methotrexate.
- Mesna reduces hemorrhagic cystitis caused by cyclophosphamide and ifosfamide.
- Dexrazoxane reduces anthracycline-induced cardiotoxicity.
- Filgrastim reverses neutropeniac aused by many anticancer agents.
- Amifostine is a cytoprotective agent that reduces renal toxicity caused by cisplatin.
6
Q
ANTIMETABOLITES
A
- FOLATE ANALOGS
- PURINE ANALOGS
- PYRIMIDINE ANALOGS
7
Q
MTX
A
- folate analog
- DHR inhibitor
- Methotrexate undergoes conversion to a series of polyglutamates (MTX-PGs).
- The process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS).
- MTX-PGs increase the inhibitory potency of MTX for additional sites, including thymidylate synthase and enzymes of the de novo purine nucleotide biosynthetic pathway.
8
Q
MTX - Adverse
A
- Common: Stomatitis, mucositis, myelosuppression, alopecia, nausea, vomiting.
- Renal Damage: Uncommon. Complication of high-dose methotrexate.
- Hepatic fibrosis and cirrhosis.
- Pneumonitis.
- Neurologic Toxicities. With IT administration.
9
Q
Leucovorin
A
- Leucovorin is N5-formyl-THF.
- Antidote to drugs that decrease levels of folic acid, such as methotrexate, to rescue the bone marrow.
- Leucovorin provides the normal tissues with the reduced folate, thus circumventing the inhibition of DHFR.
10
Q
Purine analogs
A
- 6-MP
- 6-Thioguanine
11
Q
6-MP
A
- Thiol analog of hypoxanthine.
- Converted to thio-IMP by th esalvage 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 from incorporation of guanylate analogs.
PK
- metabolized by Xanthine Oxidase to yield thiouric acid
- also metabolized by TPMT
- If allopurinol is given to reduce hyperuricemia, dose of 6-MP must be decreased to avoid accumulation of the drug.
Uses: ALL
12
Q
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.
- Used for acute non-lymphocytic leukemias.
- Allopurinol does not potentiate 6-TG action because very little is metabolized to thiouric acid.
- Toxicities: same as for 6-MP.
PK
- 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.
13
Q
Pyrimidine analogs
A
- 5-FU
- Capecitabine
- Cytarabine
- Gecitabine
14
Q
5-FU
A
- Carbecitabine is prodrug
- 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.
**MOA: **Thymidylate synthase inhibition
- Leucovorin potentiates 5-FU (but inhibits MTX)
Uses
- 5-FU is used in the treatment of carcinomas of the breast and GI tract.
- 5-FU can be used topically for keratoses and superficial basal-cell carcinoma.
- 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-FU. **
Metabolism
- 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.
15
Q
5-FU: Adverse
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.
16
Q
Capecitabine
A
- Fluoropyrimidine carbamate.
- Orally available prodrug of 5-FU.
- Capecitabine’s cytotoxic activity is the same as that of 5-FU.
17
Q
Cytarabine (ARA-C)
A
- Analog of deoxycytidine.
- Sequentially phosphorylated to the trisphosphate.
- Incorporated into DNA.
- The incorporated residue inhibits DNA polymerase.
18
Q
Gemcitabine
A
- Analog of deoxycytidine.
- Anti-metabolite -> cell cycle non-specific
**MOA: **
- Phosphorylatedbynucleosidekinasestothe nucleoside di- and triphosphate, which inhibit DNA synthesis.
- Inhibitionresultsfromtwoactions:
- Inhibition of ribonucleotide reductase.
- Incorporation of gemcitabine triphosphate into DNA. This results in chain termination.
19
Q
ANTITUMOUR ANTIBIOTICS
A
- Bind to DNA through intercalation between bases and block synthesis of new RNA or DNA (or both), cause DNA strand breakage, and interfere with cell replication.
- includes anthracyclines & bleomycin
20
Q
Anthracyclines
A
- includes doxorubucin & daunorubicin
- The anthracycline antibiotics are among the most important antitumor agents.
- Doxorubicin is one of the most widely used anticancer drugs.
MOA: 4 major mechanisms:
- 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.
21
Q
Anthracyclines: Adverse
A
- Myelosuppression: main toxicity.
- Cardiotoxicity:
- Dose-dependent, dilated cardiomyopathy associated with heart failure.
- Due to free radicals.
- The iron-chelating agent dexrazoxane can reduce the cardiotoxicity.
- “Radiation recall reaction” with erythema at sites of prior radiation therapy.
22
Q
Bleomycin
A
- Mixture of glycopeptides.
- Like the antracyclines, bleomycin causes breakage of DNA by oxidative processes.
- Cell-cycle specific. Arrest cells in G2 phase.
MOA
- A DNA-bleomycin-Fe2+ complex undergoes oxidation to bleomycin- Fe3+.
- The liberated electrons react with O2 to form free radicals which cause strand breakage.
23
Q
Bleomycin: Adverse
A
- The most serious adverse reaction is pulmonary toxicity (pneumonitis, fibrosis).
- Dose-limiting.
- Very little myelosuppression.
24
Q
Alkylating agents
A
includes
- nitrogen mustards (mechlorethane, cyclophosphamide, Ifosfamide, melphalan)
- alkyl sulfonates
- nitrosoureas
- triazenes
- methylhydrazines
- 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 bi- functional.
- Toxicities occur particularly in rapidly growing tissues like the bone marrow, GI tract and gonads.
- Nausea and vomiting are common.
- Emetic effects can be reduced with 5-HT3 receptor antagonists.
- Alkylating agents are mutagenic and carcinogenic.
- Cyclophosphamide is the most widely used alkylating agent.
25
Q
Mechlorethamine including Adverse
A
- Very unstable.
- Solutions must be made up just prior to administration.
- Powerful vesicant. Only given IV.
Adverse
- Severe nausea and vomiting.
- Severe bone marrow depression.
- Alopecia.
- Immunosuppression.
- Largely replaced by cyclophosphamide, melphalan and other more stable alkylating agents.
27
Q
Cyclophosphamide - Adverse
A
- Nausea and vomiting
- Bone marrow depression
- Hemorrhagic cystitis
- Alopecia
- Sterility
- Acrolein, a metabolite of cyclophosphamide is responsible for the hemorrhagic cystitis caused by therapy with cyclophosphamide.
- This can be prevented by parenteral administration of mesna, a sulfhydryl compound which reacts with acrolein in the bladder.
53
Q
Inhibitors of EGF Receptors
A
- Gefitinib:
- Erlotinib:
- Lapatinib: Inhibitor of EGFR and ErbB2 tyrosine kinases.
- Cetuximab: mAb against EGFR
- Trastuzumab: mAb against ErbB2
54
Q
Imatinib
A
Inhibits the tyrosine kinase of Bcr-Abl. Inhibits c-kit (a receptor tyrosine kinase.)
55
Q
Sorafenib
A
- Inhibits the serine/threonine kinase RAF, which is immediately downstream of RAS
- also inhibits VEFR-2, PDGFR and other RTK so it also inhibits angiogenesis
56
Q
Bortezomib
A
- Inhibits the proteasome.
- Induces growth inhibition and apoptosis of tumor cells with relatively few toxic effects on normal cells.
57
Q
Sunitinib
A
- Inhibits VEGFR-1, VEGFR-2, and PDGFR
58
Q
ASPARAGINASE
A
- Most normal tissues synthesize L-asparagine in amounts sufficient for protein synthesis.
- Certain neoplastic tissues, however, require exogenous source.
- Asparaginase hydrolyzes serum asparagine, depriving these cells of the asparagine necessary for protein synthesis, leading to cell death.
