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Flashcards in Anticancer drugs Deck (23):
1

Alkylating agents

-Nitrogen mustards: mechlorethamine, cyclophosphamide
-Nitrosoureas: carmustine, semustine, lomustine, streptozotocin
-Platinum compounds: cisplatin, carboplatin
-Methylating agents: procarbazine
-All alkylating agents covalently bind to N7 on guanine residues in DNA
-This causes intra or inter-strand cross-linkages and base pair substitution
-Base pair substitution responsible for mutagenic and carcinogenic effects
-Proliferation-dependent and cell-cycle phase non-specific drugs

2

Nitrogen mustards

-Mechlorethamine: nonenzymatic activation, used for Hodgkin's lymphoma (part of MOPP treatment)
-Mechlorethamine is highly reactive (unstable), freshly prepared, given IV
-Cyclophosphamide: broad uses, activated by CYP450 in the liver (protected by inactivated metabolite)
-Advantages of a prodrug: slowly releases just enough of active metabolite to limit side effects
-Can cause hemorrhagic cystitis: toxicity to bladder, causes pink urine (RBCs), induced by acrloein (metabolite). Can Rx w/ thiol agents, mesna, N-acetylcystein
-Cyclopohosphamide interacts w/ allopurinol (Rx of gout) since allopurinol decreases P450 activity, tis prolonging the half-life of cyclophosphamide (decrease dose)

3

Resistance to alkylating agents

-Increased drug inactivation due to cellular thiol/glutathione
-Decreased drug uptake
-Increased activity of DNA excision repair nzs

4

Nitrosoureas

-Carmustine, semustine, lomastine: all are synthetic, non enzymatic drugs used for brain metastases
-They are lipophilic and cross BBB to alkylate DNA, also react w/ proteins and DNA repair nzs (carbamoylates them)
-Streptozotocin is a nonsynthetic, non enzymatic drug used for pancreatic islet cell carcinomas
-It is taken up by islet cells and destroys them, causing diabetes (diabetogenic)

5

Platinum compounds

-Cisplatin: many uses, is a non enzymatic drug that displaces chloride to become activated
-It causes nephro and ototoxicity, but low myelosuppression (preferred)
-Caboplatin: few uses (only when cisplatin is toxic), is non enzymatic
-Causes no nephro or ototoxicity but does cause myelosuppression

6

Methylating agents

-Procarbazine: A prodrug (activated by P450, MAO) that is used for Rx of Hodgkins lymphoma (part of MOPP)
-Inhibits P450, and monoamine oxidase (which breaks down monoamines)
-Procarbazine and tyramine-containing foods (cheese, yogurts, beer, wine): procarbazine inhibits MAO (which inactivates tyramine and norepinephrine), resulting in their elevation and hypertension
-Procarbazine and antidepressants: procarbazine inhibits P450 and potentiates the effects of phenothiazine, barbiturates, and narcotics

7

Antimetbolites

-Two mechanisms of action: inhibition of DNA precursors (and ultimately DNA synthesis) and/or substitution for normal bases in DNA/RNA and alter their function
-All are cell-cycle phase specific (act in S phase)

8

Hydroxyurea

-Antimetabolite that inhibits ribonucleotide reductase
-Results in inhibition of synthesis of DNA precursors
-Synchronizes cells and enhances radiation effects (S phase specific)

9

Methotrexate

-Analog of folate, not a prodrug but activity can be furthered by polyglutamate. Cell-cycle phase specific (requires S-phase)
-Inhibits DHF (dihydrofolate) reductase (direct) and decreases synthesis of methyl donor (THF) for thymidylate synthesis (indirect). Can inhibit synthesis of purines
-At high doses it can overcome tumor resistance
-Host tissues protected by leucovorin
-Resistance caused by gene amplification (increased DHF reductase), and/or altered DHFR w/ decreased affinity for drug. Also decreased uptake
-Interaction btwn methotrexate and salicylate (aspirin) or sulfonamide: both displace methotrexate from albumin and inhibit its tubular secretion (increasing plasma levels and toxicity). Avoid the combination, give leucovorin to aid toxicity

10

5-fluorouridine

-Analog of uracil, prodrug w/ multistep activation (to FdUMP). Cell cycle specific (S phase)
-Inactivates thymidylate synthase by covalently binding (folate is required)
-Inhibits DNA synthesis of DNA precursors and incorporates into RNA but not DNA
-Decreased affinity of thymidylate synthase for FdUMP, increased thymidylate synthase
-Used in many cancers

11

5-fluorodeoxyuridine

-Analog of deoxyuridine, prodrug w/ 1 set activation (to FdUMP). Cell cycle specific (S phase)
-Inactivates thymidylate synthase by covalently binding (same mech. as 5FU)
-Inhibits DNA synthesis of DNA precursors and incorporates into RNA but not DNA
-Rapidly hydrolyzed in the cell, limited applications
-Used in liver, head, and neck tumors

12

Purine antagonists (thiopurines)

-Includes 6-mercaptopurine (analog of hypoxanthine) and 6-thioguanine (analog of guanine)
-These are prodrugs that are activated by HRPTase (hypoxanthine-guanine phosphoribosyl transferase), which converts mercaptopurine into thio-IMP and thioguanine into thio-GMP
-These thionucleotides inhibit purine synthesis in 2 places: (1) the first committed-step in the purine pathway (amidophophoribosyl transferase), and (2) the branching point where IMP is channeled to AMP and GMP (IMP dehydrogenase)
-Are self-limiting drugs

13

Mechanism, resistance, and interaction of thiopurines

-Both of the thiopurines inhibit synthesis of purine precursors
-ThioGMP (made eventually from both 6-mercaptopurine and 6-thioguanine) is incorporated into RNA and DNA
-This alters RNA properties and maturation, and changes DNA-protein interaction and its replication
-Resistance can be due to deletion of HPRTase (first activating nz) and/or an increase in membrane-bound alkaline phosphatase
-Allopruinol decreases inactivation of 6-MP by inhibiting xanthine oxidase, thus prolonging the half-life of 6-MP and increasing toxicity (decrease dose of 6-MP to 25%)

14

Cytarabine

-An analog of deoxycytidine, and a prodrug which is activated to Ara-CMP by deoxycytidine kinase (Ara-CMP further converted into Ara-CTP)
-Ara-CTP is a substrate for DNA polymerase and incorporates into DNA in place of dCTP (no effect on RNA). At sufficient incorporation, DNA synthesis is terminated (new mech.)
-At high enough concentrations Ara-CTP inhibits DNA polymerase by competing w/ dCTP
-Does not inhibit precursor synthesis
-Used in acute leukemia, but not solid tumors

15

Side effects and resistance to Cytarabine

-Can cause cerebral dysfunction (high levels in CSF due to lack of deaminase nz): ataxia, lack of coordination, confusion, seizures, coma
-Resistance can occur from decreased deoxycitine kinase (activating nz), and/or increased deoxycytidine deaminase (inactivating nz)

16

Vinca alkaloids

-Bind to tubulin dimer and prevent tubulin polymerization and enhance depolymerization (forms paracrystalline aggregates)
-This results in the net dissolution of mitotic spindle and results in arrest of tumor cells in metaphase (cell-cycle specific, "spindle poisons")
-Includes vincristine (broad spectrum but causes neuropathy and GI problems) and vinblastine (limited use b/c of myelosuppression)
-Resistance induced b/c of mutations in tubulin, amplification of p-glycoprotein gene (increased drug efflux)
-Used in MOPP regimen for Hodgkin's (O= oncovin= vincristine)

17

Paclitaxel (Taxol)

-Binds to polymerized tubulin and prevents depolymerization (arrests cells in metaphase- cell cycle specific)
-Used in tumor cells resistant to vinca alkaloids
-Mostly in ovarian and breast cancer

18

Etoposide

-Inhibits topoisomerase II and increase DNA breakdown
-Blocks the cell at G2 stage (cell cycle specific)
-Used in testicular tumors mostly, plus some others

19

Anthracyclines

-Cause DNA intercalation: bind btwn bases and decrease DNA and RNA synthesis (arrest in G2 phase: cell cycle specific)
-Also cause: DNA strand breaks (inhibit topo2), membrane fluidity changes, generation of ROS
-Resistance: due to over expression of P-glycoprotein (increased drug efflux)
-Doxorubicin: broad applications for both hematological and solid tumor malignancy
-Daunorubicin is only useful in leukemia (hematological, not used for solid tumors)
-Other side effect: cardiomyopathy caused by ROS generation
-Has an asymptomatic period, followed by tachycardia and SOB, then CHF (do biopsy to check)
-Risk factors: total dose >550, radiotherapy to heart, cyclophosphamide
-Used in CHOP therapy for Hodgkin's

20

Bleomycin

-Binds Fe3+ or Cu2+. The complex is then reduced in the nucleus and the reduced metal reacts w/ O2 to make ROS
-The generated ROS cause DNA strand breaks (inhibit G2 phase of cell cycle)
-Resistance: over expression of P-glycoprotein (increased efflux)
-Other side effect: Pulmonary fibrosis due to low bleomycin-hydrolyzing nz
-Causes Dyspnea, cough, bilateral infiltrates on Xray, hypoxic symptoms, inflammation + fibrosis
-Radiotherapy to chest, renal failure (decreases excretion), and 100% O2 therapy (O2 limits ROS production) all increase risk

21

Myelosuppressor exceptions

-Drugs that are not toxic to bone marrow
-Streptozotocin
-Vincristine
-Bleomycin

22

Combination therapy

-Drugs are used in combination that act thru different mechanisms, do not overlap toxicity, and do not display cross-resistance
-MOPP for Hodgkins: Mechlorethamine, vincristine (oncovin), procarbazine, prednisone
-CHOP for Hodgkins: Cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (oncovin), prednisone
-FAC for breast cancer: Cyclophosphamide, doxorubicin (adriamycin), fluorouracil

23

Side effects of all anticancer drugs

-Cytotoxic to all rapidly dividing cells (GI epithelia)
-Bone marrow suppression (leukopenia, thrombocytopenia, anemia)
-Loss of hair (destruction of hair follicles, alopecia)
-Nausea/vomiting (CNS origin, reduced by pot, dronabinol or THC)
-Mutagenic, teratogenic, carcinogenic (can cause leukemia)
-Immunosuppressive (can lead to opportunistic infection)