Anticancer drugs Flashcards
1
Q
Alkylating agents
A
- 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
Q
Nitrogen mustards
A
- 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
Q
Resistance to alkylating agents
A
- Increased drug inactivation due to cellular thiol/glutathione
- Decreased drug uptake
- Increased activity of DNA excision repair nzs
4
Q
Nitrosoureas
A
- 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
Q
Platinum compounds
A
- 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
Q
Methylating agents
A
- 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
Q
Antimetbolites
A
- 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
Q
Hydroxyurea
A
- Antimetabolite that inhibits ribonucleotide reductase
- Results in inhibition of synthesis of DNA precursors
- Synchronizes cells and enhances radiation effects (S phase specific)
9
Q
Methotrexate
A
- 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
Q
5-fluorouridine
A
- 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
Q
5-fluorodeoxyuridine
A
- 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
Q
Purine antagonists (thiopurines)
A
- 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
Q
Mechanism, resistance, and interaction of thiopurines
A
- 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
Q
Cytarabine
A
- 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
Q
Side effects and resistance to Cytarabine
A
- 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
Q
Vinca alkaloids
A
- 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
Q
Paclitaxel (Taxol)
A
- 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
Q
Etoposide
A
- 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
Q
Anthracyclines
A
- 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
Q
Bleomycin
A
- 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
Q
Myelosuppressor exceptions
A
- Drugs that are not toxic to bone marrow
- Streptozotocin
- Vincristine
- Bleomycin
22
Q
Combination therapy
A
- 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
Q
Side effects of all anticancer drugs
A
- 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)