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.
26
Q
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
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.
28
Q
IFOSFAMIDE including Adverse
A
- Analog of cyclophosphamide.
- Activated by hydroxylation in the liver by CYP3A4
Adverse
- Similar toxicity profile to cyclophosphamide, but causes greater platelet suppression, neurotoxicity, and urinary tract toxicity.
- Adequate hydration and administration of mesna permit its use.
29
Q
Melphalan
A
Primarily used to treat multiple myeloma.
30
Q
Alkyl sulfonate
A
BUSULFAN
- Mainly used in chronic myelogenous leukemia.
- Myelosuppression is the main toxicity.
- May cause pulmonary fibrosis.
31
Q
Nitrosoureas
A
CARMUSTINE
LOMUSTINE
- Very lipophilic.
- Cross the blood-brain barrier.
- Useful in treatment of brain tumours.
- Nitrosoureas require biotransformation, which occurs non-enzymatically.
32
Q
TRIAZENES
A
DACARBAZINE
- Acts as methylating agent after activation in the liver.
- Given IV.
- Indicated for malignant melanoma.
- Also indicated for Hodgkin’s disease.
- Toxicity includes nausea and vomiting.
- Myelosuppression is usually mild to moderate.
33
Q
PROCARBAZINE
A
- METHYLHYDRAZINES
- Converted by liver P450 enzymes to alkylating metabolites.
USES
- Used in combination with mechlorethamine, vincristine and prednisone (the MOPP regimen) for the treatment of Hodgkin’s disease.
- Alternative regimens with less leukemogenic potential have replaced MOPP.
34
Q
PROCARBAZINE: ADVERSE EFFECTS
A
- Leukopenia and thrombocytopenia.
- MAO inhibitor
- Disulfiram-like reactions.
- Highly carcinogenic, mutagenic and teratogenic.
- Potent immunosuppressive agent.
35
Q
PLATINUM COORDINATION COMPLEXES
A
- CISPLATIN
- CARBOPLATIN
- 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. **
- Inhibit DNA synthesis and binds DNA through formation of cross-links.
- Given IV.
Uses
- Approved for testicular, ovarian, and bladder cancers.
- Its use with vinblastine and bleomycin has been major advance in development of curative therapy for testicular cancers.
36
Q
CISPLATIN: ADVERSE EFFECTS
A
- Myelosuppression: mild-to-moderate.
- Nausea and vomiting.
- Ototoxicity.
- Peripheral neuropathy.
- Nephrotoxicity is abolished by hydration and diuresis.
- Amifostine is a cytoprotective agent used to reduce the renal toxicity associated with cisplatin.
37
Q
Carboplatin - Adverse
A
- Less nausea, neurotoxicity, ototoxicity and nephrotoxicity than cisplatin.
- Dose-limiting toxicity is myelosuppression.
38
Q
MT inhibitors
A
- Vinca alkaloids: vincristine & vinblastine
- Taxanes: Paclitaxel & Docetaxel
39
Q
Vinca alkaloids including Adverse
A
- includes vincristine and vinblastine
MOA
- Vinca-tubulin and inhibit its ability to polymerize into microtubules.
- This results in mitotic arrest in metaphase.
- Cell division stops. Cells die by apoptosis.
Adverse
- Vincristine: Peripheral neuropathy. Bone marrow depression is mild. Alopecia.
- Vinblastine: Myelosuppression is the dose- limiting adverse effect. Other adverse effects include alopecia and peripheral neuropathy
40
Q
Taxanes
A
- including Paclitaxel & Docetaxel
MOA
- Taxanes bind to beta-tubulin subunit of microtubules and promote microtubule polymerization.
- Stabilization of the microtubules in a polymerized state arrests cells in mitosis and leads to apoptosis.
41
Q
Taxanes - Adverse
A
PACLITAXEL
- Hypersensitivity,myelosuppression,peripheral neuropathy, alopecia, etc
- Hypersensitivity is reduced by premedication with dexamethasone, diphenhydramine and an H2 blocker
- Abraxane is an albumin-bound form of paclitaxel which does not cause hypersensitivity, does not require premedication, and causes less myelosuppresion than the traditional paclitaxel.
DOCETAXEL
- Myelosuppression, peripheral neuropathy, fluid retention, alopecia, mucositis.
- Pretreatment with dexamethasone is required to prevent fluid retention.
- Docetaxel does not cause neuropathy as frequently as paclitaxel.
- Myelosuppression is dose-limiting.
42
Q
Epipododphyllotoxin
A
43
Q
Camptothecin
A
- TOPOTECAN
- IRINOTECAN
- Natural products derived from the Camptotheca acuminata tree.
- Inhibit topoisomerase I. Inhibition results in DNA damage.
44
Q
Relative myelosupression
A
High
- Cytarabine
- Alkylating agents
- Doxorubicin
- Daunorubicin
- Vinblastine
Medium
- Carboplatin
- MTX
- 5-FU
Low
- Bleomycin
- Vincristine
- Asparaginase
45
Q
ESTROGEN INHIBITORS
A
Anti-estrogen approaches for therapy of hormone-positive breast cancer include:
- SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERMs): Tamoxifen, Raloxifene
- SELECTIVE ESTROGEN-RECEPTOR DOWNREGULATORS (SERDs): Fulvestrant
- AROMATASE INHIBITORS (AIs): Anastrozole & Letrozole, Exemestane
46
Q
TAMOXIFEN
A
- SERMS bind to estrogen receptors and act as agonists or antagonist depending on the tissue.
- Tamoxifen is an antagonist on breast cancer.
- Tamoxifen is an agonist in nonbreast tissues.
- Used for receptor-positive breast cancer.
- Chemopreventive agent in women at risk for breast cancer.
47
Q
RALOXIFENE
A
- Raloxifene is an antiestrogen in the uterus and the breast, while promoting estrogenic effects in the bone to inhibit resorption.
- Used for prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in high risk postmenopausal women.
48
Q
FULVESTRANT
A
- SERDs are devoid of estrogen agonist activity.
- Fulvestrant binds to the estrogen receptor (ER) inhibits its dimerization and increases its degradation.
- ER-mediated transcription is abolished.
49
Q
AROMATASE INHIBITORS
A
- Aromatase converts androstenedione to estrone.
- In postmenopausal women, this conversion is the primary source of circulating estrogens.
- Aromatase inhibitors are the standard of care for adjuvant treatment of postmenopausal women with hormone receptor–positive breast cancer.
ANASTROZOLE & LETROZOLE
- Nonsteroidal.
- Reversiblecompetitiveinhibitorsofaromatase.
EXEMESTANE
- Steroidal.
- Irreversibleinhibitorofaromatase.
50
Q
ANDROGEN INHIBITORS
A
- The preferred approach for the therapy of prostate cancer is the use of GnRH agonists, alone or in combination with an androgen receptor blocker.
- GONADOTROPIN-RELEASING HORMONE AGONISTS
- ANDROGEN RECEPTOR BLOCKERS
51
Q
GONADOTROPIN-RELEASING HORMONE AGONISTS
A
- GOSERELIN
- LEUPROLIDE
- When given continuously or as a depot, GnRH agonists cause an initial surge in LH and FSH levels, followed by inhibition of gonadotropin release.
- This results in reduction of testicular production of testosterone to castrate levels.
- Testosterone levels fall to 10% of their initial values after a month.
- However,they increase significantly in the beginning, causing a transient flare of tumor activity and an increase in symptoms.
- The flare phenomenon can be counteracted by concurrent administration of flutamide for 2-4 weeks.
52
Q
FLUTAMIDE
A
- ANDROGEN RECEPTOR BLOCKERS
- Synthetic, nonsteroidal antiandrogen.
- Metabolized to an active metabolite that acts as a competitive antagonist at the androgen receptor, preventing its translocation to the nucleus.
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.
59
Q
ASPARAGINASE - ADVERSE EFFECTS
A
- Hypersensitivity.
- Decrease in clotting factors.
- Liver abnormalities.
- Pancreatitis, seizures, coma due to ammonia toxicity.
60
Q
HYDROXYUREA
A
- Inhibits ribonucleotide reductase.
- This leads to depletion of deoxynucleoside trisphosphate pools.
- DNA synthesisis thereby inhibited.
- Kills cells in S phase.
- Given orally.
- **Uses: **Melanoma, chronic myelocytic leukemia, carcinoma of the ovary, head and neck.
61
Q
Interferons alpha
A
Approved for hairy cell leukemia, CML, malignant melanoma and Kaposi’s sarcoma.
