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)
