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62 Cards in this Set

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Inhibitors of DHFR (Folic Acid Analogues)?
MethoTREXate
PremeTREXed
PralaTREXate
5-Fluorouracil MOA?
Inhibition of Thymidylate Synthetase (stable Ternary Complex)

Combo w/Leucovorin --> synergistic effect
How does Leucovorin exert synergistic effects with 5-FU?
Increases binding of 5-FU to Thymidylate Synthetase --> more Ternary complexes formed
What is Leucovorin Rescue?
Combination of LV + MTX to combat toxicities

Only normal cells take up LV --> use LV to bypass blocked DHFR pathway --> can still make Thymidine for DNA
What cell cycle phase are antimetabolites selective for?
CCSS: Cell Cycle Selective for S phase
Methotrexate MOA?
Inhibit thymidine synthesis by blocking dihydrofolate reductase

1000x higher affinity for DHFR: R-NH3+ more protonated --> forms salt bridge w/Asp in active site.
List Pyrimidine Analogs covered in class.
5-fluorouracil
Capecitabine (prodrug of 5-FU)
Gemcitabine
List Purine Analogs covered in class.
6-Mercaptopurine
Thioguanine (no longer used)
Fludarabine Phosphate
Deoxycoformycin
Chloroadenosine
Hydroxyurea
L-Asparaginase (Pegasparaginase) MOA?
Hydrolyze asn --> Deprives LYMPHOBLASTS of exogenous asn --> decrease growth rate

other cell types don't need exogenous Asn; make their own
Therapeutic application of L-Asparaginase?
ALL

Acute Lymphoblastic Leukemia
Therapeutic benefit of L-Asparaginase?
It's an enzyme --> no BMD, doesn't penetrate bone

rarely allergic reactions; hepatotoxicity, pancreatitis
Therapeutic application of Deoxycoformycin?
Hairy Cell Leukemia (very rare)
Drug-drug interaction of 6-MP with Allopurinol?
Allopurinol blocks Xanthine Oxidase --> decreased metabolism of 6-MP --> more BMD

must decrease dose of 6-MP ~40% to avoid severe BMD
Genetic factors involved in 6-MP Toxicities?
Thiomethyl Transferase enzymes: methylates and detoxifies 6-MP

Slow methylators more at risk for severe BMD
MOA of purine analogs?
Analogs of A/G precursor --> interfere w/DNA synth at MANY steps (too many to list)
Which normal cells are constantly dividing and thus casualties of chemotherapy tx that target rapidly proliferating cells?
1. GI mucosa
2. Bone Marrow derived cells (esp neutrophils)
3. Hair follicles
4. Reproductive germ cells
Special tox of antimetabolites (folic acid analogs)?
Kidney damage due to pptn of 7-OH metabolite in renal tubules.

Minimize this by giving NaHCO3 --> form soluble salt of mtx
MOA of Nitrogen mustards?
DNA alkylation via x-linking with reactive AZIRIDINIUM ION
Special tox and management of cyclophosphamide and Ifosphamide?
Hemorrhagic cystitis due to metabolite ACROLEIN forming cysteine conjugates w/bladder epithelium

--> take with MESNA; acts as cys surrogate.
MOA of Lomustine?
Nitrosurea

DNA Alkylation via diazonium and aziridinium ions.
Advantage of Temodar?
Prodrug of Dacarbazine, available PO!

CCNS
Etoposide, Teniposide
MOA?
General Tox?
CCS?
Examples?
bind topoisomerase II --> DNA strand breaks

BMD (allergic rxns)

CCS-S/G2

Epi-podophyllotoxins
Doxorubicin (Adriamycin)
MOA?
Tox?
CCS?
Anthracycline abx
MOA: 1. inhibit topo II
2. Intercalate DNA, quinone reduction --> O2 radicals --> strand breaks

Tox = BMD, Cardiotoxicity

CCNS b/c dual MOA
Epirubicin

What is it?
Same as Doxorubicin but -OH is "up" on sugar ring (epimer of doxorubicin)

for breast cancer
Topotecan (Hycamtin)
MOA?
Tox?
CCS?
MOA = binds topo I --> can't unwind DNA --> strand breaks

Tox = BMD, hypersensitivity

CCS-S/G2
Irinotecan

Metabolic Effects?
Special tox?
CCS?
PRODRUG! hydrolyzed to phenol, phenol is glucuronidated,

Special tox = severe diarrhea.
speed of glucuronidation ∝ severity of BMD, diarrhea

CCS-S and G2
Topoisomerase I inhibitors
MOA?
Tox?
CCS?
MOA = binds topo I --> can't unwind DNA --> strand breaks

Tox = BMD, hypersensitivity

CCS-S/G2
Vinblastine, Vincristine
MOA?
Tox?
CCS?
MOA = binds tubulin dimers, prevents polymerization of microtubules --> inhibit mitosis

Tox = VC: CNS (peripheral neuropathy) VB: BMD

CCS-M

Vinca Alkaloids
Taxol, Docetaxel, Cabazitaxel, Eribulen
MOA?
Tox?
CCS?
MOA = stabilizes microtubules --> can't depolymerize; inhibits BCL2 --> promotes apoptosis

Tox = BMD, peripheral neuropathy

CCS-G2/M

Taxanes (eribulen is macrocyclic ketone)
Examples of Taxanes?
Taxol (Paclitaxel)
Docetaxel (Taxotere)
Cabazitaxel (Jevtana)
Eribulin (Halaven)
Cisplatin, Carboplatin, Oxaliplatin
MOA?
CCS?
Platinum Agents/DNA Metalating Agents

MOA = x-links DNA; nucleophiles on DNA displace chloride ligands

CCNS
Mitomycin (Mutamycin, an Aziridinyl Quinone)
MOA?
Tox?
CCS?
MOA = DNA x-linking due to reductive metabolism of quinone, aziridine, carbamate groups.

Tox = BMD; lung/liver damage

CCNS
Procarbazine

MOA?
Tox?
CCS?
DDI's?
MOA = prodrug; metabolized to diazonium ion --> methylates DNA

Tox = BMD

CCNS

DDI's: inhibits MAOI --> heart arrhythmia w/sudafed, wine, cheese
Special tox and sefx of Cisplatin?
tox = kidney damage (no BMD)

sefx = N/V, ototoxicity, electrolyte imbalance due to kidney damage
Chief clinical use of (Peg)Asparaginase?
ALL
(Acute Lymphoblastic Leukemia, childhood)

Only lymphoblasts require exogenous Asparagine.
Chief clinical use of Bicalutamide?
Prostate Cancer

Blocks androgen receptor. Bicalutamide is newer analog of Flutamide; nitrile group limits toxicity
Chief clinical use of Tamoxifen?
Estrogen-Dependent Breast Cancer
Chief clinical use of Anastrozole?
Breast cancer

Aromatase inhibitor: binds aromatase tightly
Chief clinical use of Exemestane?
Breast Cancer.

Suicide aromatase inhibitor.

MOST effective preventative tx for breast cancer available.
Ixabepilone, Eribulin
MOA?
Tox?
CCS?
MOA: Bind/stabilize microtubules, stop inhibition of apoptosis

Tox = BMD, neuropathy

CCS-M and G2

Epothilones. Ixa from myxobacterium; Eri from sea sponges
Cyclophosphamide
MOA?
Activation by oxidative N-dealkylation, base-catalyzed elimination of acrolein to form Phosphoramide Mustard.

P. Mustard --> aziridinium ion mecha
What are the steps of carcinogenesis?
1. Initiation
2. Promotion
3. Progression (metastasis)
What happens during initiation phase?
DNA damage: strand breakage, base deletion, mutations, xsome rearrangement, aneuploidy

Mutated TUMOR SUPPRESSOR genes
What happens during Promotion phase?
Conversion of initiated cell to malignant phenotype; clonal expansion of this cell

Mutated PROTO-ONCOGENES --> Expression of ONCOGENES
What happens during Progression phase?
Tumor formation
Invasion of tissues
Metastasis
What types of genes are most commonly implicated in carcinogenesis?
Proto-Oncogenes (can mutate to become oncogenes)

Tumor Suppressor genes (get inactivated, leading to uncontrolled proliferation)
Hereditary factors are implicated in about ______ of all cancers.
half (~50%)
Cigarette smoke is associated with _________ of all cancers.
~30%
What type of drug ends in -ib?
Tyrosine Kinase Inhibitor
Leuprolide
MOA?
Tox?
Sefx/DDI?
MOA: GnRH analog --> suppresses FSH/LH --> decrease androgens

Sefx = Feminization; hot flashes, etc.
Cyclosporine, Tacrolimus
MOA?
Tox?
Sefx/DDI?
Immunosuppressant for organ/bone marrow transplants; decrease T lymphocyte activation

Tox = Nephro/hepatotoxicity

DDI = CYP3A inhibitors
Interferons α-2a, α-2b
MOA?
Tox?
Sefx/DDI?
Activate RNAses --> degrade mRNA produced by oncogenes

Tox = flu-like anaphylaxis, hypoTN, tachycardia, liver failure

DDI = these are P450 inhibitors.
Interleukin IL-2
MOA?
Tox?
Sefx/DDI?
Cytokine that transforms T cells into Lymphokine Activated Killer cells.

Tox = hypotension, pulmonary + peripheral edema
Interleukin IL-1
MOA?
Tox?
Sefx/DDI?
Cytokine that enhances platelet recovery after carboplatin tx (which kills off platelets)
G-CSF, GM-CSF
MOA?
Sefx/DDI?
Recombinant hematopoeitic growth factor, stimulates bone marrow production of granulocytes (+monocytes) --> increase WBC.

Sefx = fever, flu-like symptoms
Amifostine
MOA?
Sefx/DDI?
Thiophosphate; hydrolyzed by alk phos --> aminothiol that protects from cisplatin nephro/ototoxicities, decreases BMD w/carboplatin, paclitaxel, etc.
Prednisone/Dexamethasone
MOA?
Tox?
Sefx/DDI?
Anti-inflammatory. Also bind intracellular GC-R (transcription factor) --> proteins that decrease DNA/RNA synth

Appetite stimulant

Tox = increased chance of infections due to immunosuppression; psychoses, cushing's syndrome
Trend observed with toxicities of Platinum Complexes?
Increasing lipophilicity --> increasing tissue penetration

Also get BMD as penetration increases

All have kidney and acoustic nerve damage, periph neuropathy
Bleomycin
MOA?
Tox?
CCS?
MOA = intercalates DNA, heme like structure chelates Fe+, binds Oxygen --> O radicals --> DNA strand breaks.

Tox = lung damage (no BMD)

CCS-S and G2 phases
Special tox of carmustine and lomustine?
Pulmonary Fibrosis due to nitroso group

Dose limiting tox = BMD though
Steps in Lomustine MOA?
1. Base catalyzed amide hydrolysis

2. Dehydration of Hydroxydiazene to form Diazonium ion

3. Nucleophilic displacement of N2
Steps in Dacarbazine reaction w/DNA?
1. Oxidative N-Dealkylation

2. Tautomerization to N-N=N-CH3

3. Methylation of DNA, elimination of N2