antimetabolites/alkyl groups

Question 1

Methotrexate

Answer 1

• Mech of Action:
• inhibits Dihydrofolate reductase –> reduces precursors for RNA and DNA synthesis
• LEUCOVORIN is used to reduce methotrexate toxcity at an otherwise lethal dose
• RESISTANCE:

–> Decreased transport of methotrexate into cells

–> mutations in DHFR that reduce its affinity for methotrexate

–> elevated DHFR expression (gene amplification)

TOXCITIES: interstitial pneumonitis, Nephrotoxity, hepatic dysfunction

Question 2

5-Fluorouracil (5-FU)

Answer 2

• Mech of action:
• incorporated into DNA and RNA –> inhibited synthesis and function
• inhibits thymidylate synthetase –> reduces DNA precursors
• USE: frequently used agent in tx of GI-cancers including colorectal and stomach

ADVERSE: Oral and GI ulcers

Question 3

Cytarabine (ara-C)

Answer 3

• MECH OF ACTION (only active in S-phase)
• Incorporated into DNA and RNA –> inhibits synthesis and function
• inhibits DNA synthesis by inhibiting DNA Polymerase
• TX of: Acute myelogenous leukemia (only used to tx hematologic malig)

ADVERSE: Cerebellar syndrome (dysarthria, nystagmus, ataxia)

RESISTANCE:

–> loss of deoxycytidine kinase

–> reduced transport of ara-C across cell membrane

–> cytidine deaminase upregulation –> increase ara-C inactivation

Question 4

Gemcitabine

Answer 4

• MECH OF ACTION
• incorporated into DNA, which inhibits synthesis and function
• inhibits ribonucleotide reductase (RNR) –> reduces precursors for DNA
• RESISTANCE:

–> reduced activity of deoxycytidine kinase

–> tumors increase production of deoxycytidine

Question 5

6-Thioguanine (6-TG) or 6-Mercaptopurine (6-MP)

Answer 5

• Mech of action:

–> incorporated into DNA, which inhibits synthesis and function

–> inhibit purine synthesis –> reduce precursors for RNA/DNA

• TX of acute lymphoblastic leukemia (ALL)
• RESISTANCE

–> Decreased activity of HGPRT (enzyme that activates drug)

Question 6

Fludarabine

Answer 6

• MECH OF ACTION:

–>Incorporated into DNA and RNA, which inhibits synthesis and function

–> inhibits DNA polymerase and ribonucleotide reductase (RNR)

• TX of Chronic lymphocytic leukemia (CLL)
• RESISTANCE caused by decreased activity of deoxycytidine kinase and drug efflux.

Question 7

Cladribine

Answer 7

• MECH OF ACTION

–> incorporated into DNA

–> causes strand breaks

–> potent inhibitor of ribonucleotide reductase (RNR) –> reduces DNA precursors.

• TX for Hairy cell leukemia
• RESISTANCE: decreased acitivty of deoxycytidine kinase, drug efflux and increased RNR expression

Question 8

describe the mechanisms of action of alkylating agents

Answer 8

• Mech of action:

–> Rxns between alkyl groups on drug with nucleophilic groups on proteins and nuclei acids cause DNA crosslinking leading to strand breaks

–> TOXIC IN ALL STAGES OF CELL CYCLE

Question 9

Name the alkylating agents

Answer 9

Alkylating agents:

–> Mechlorethamine

–> cyclophosphamide

–> Carmustine

Non-Classical aklylating agents

–>Cisplatin

–> carboplatin

–> oxaliplatin

Question 10

Cyclophosphamide

Answer 10

• Mech of action:

–> Cyclophosphamide is convered in liver to its active form

–> 5-10% of patients the active form is broken down into ACROLEIN (cytotoxic)

• TX with MESNA inactivates acrolein (reduces cytotoxicty
• ADVERSE: Hemorrhagic cystitis caused by acrolein, nausea, vomiting

Question 11

Carmustine (BCNU)

Answer 11

• USED in TX of Brain tumors and hodgkin’s lymphoma

–> highly lipophilic which allows it to cross the blood brain barrier

Question 12

Describe the mechanisms of resistance for alkylating agents

Answer 12

• inactivation by glutathione and other nucleophiles (increased glutathione production)
• reduced uptake
• accelerated DNA repair
• increased expression of MGMT (06-methylguanine-DNA methyltransferase)

–> prevents permanent DNA damage by removing alkyl groups from guanine before cross links form

Question 13

describe non-classical aklylating agents

Answer 13

• they lead to DNA cross-linkages, but they have no aklyl group

–> targets nucleophilic center

–> actively transported into cells via Cu2+ transporter

• TYPES:
• Cisplatin
• Carboplatin
• oxaliplatin

Question 14

describe adverse effects of CISPLATIN vs Carboplatin

Answer 14

• CISPLATIN:

–> mild myelosuppression

–> neuropathy, nephrotoxicity (increased hydration reduces risk)

• Carboplatin

–> LESS nausea, neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin

–> dose-limiting toxicity is MYELOSUPPRESSION

• BOTH: ANAPHYLACTIC LIKE RXNS, increased risk of leukemia