Chem II: Alkylating Agents Flashcards
Is there an advantage to using both a cell cycle specific drug and a cell cycle non-specific drug in the treatment of a patient with cancer? Explain
Describe the characteristic toxicity of the oxazophorines. Describe two strategies for preventing this characteristic toxicity
The alkylating agents do not have schedule dependent cytotoxicity. Why?
Contrast the mechanisms of action of vincristine and paclitaxel.
Which plant alkaloid is NOT a “spindle poison”?
What are the characteristics of cancer chemotherapeutic agents which might indicate that the drugs would have schedule dependent cytotoxicity?
For the drugs covered in this lecture, indicate which drugs require a dose reduction in the presence of jaundice.
For the drugs covered in this lecture, indicate which drugs require a dose reduction in the presence of renal insufficiency.
Discuss the mechanism of cytotoxicity for the bifunctional alkylating agents.
Alkalating agents bind _____ to _____
Are cell cycle ______
–> DNA drug ________ crosslinks
Alkylate at:
How can resistance occur? (2)
Alkalating agents bind covalently to the DNA
Are cell cycle NON-SPECIFIC
–> DNA drug inter AND intra - strand crosslinks
Alkylate at: N-7 guanine
How can resistance occur? enhanced DNA repair or binding to sulfur containing molecues (sulfur prevents the alkylation)
what type of reaction does cyclophosphamide undergo and where?
What metabolite is the DNA damaging agent?
How is this drug excreted? What symptoms thus can be seen at high doses?
Cyclophosphamide undergoes a microsomal oxidation reaction in the liver
After a few steps –> phosphamide mustard = DNA damaging agent
Phosphamide mustard and acrolein are excreted by the kidneys –> irritaiton to the GU epithelium –> hematuria and at high doses frank hemorrhagic cystitis
Cyclophosphamide:
Activation?
Major side effects (5):
What cancers is it used in (3):
Other drugs (2):
Activation is REQUIRED, P-450 oxidase activity
Could be given orally or IV
Side Effects: myelosuppression, N/V, hair loss, hematuria
(mitigate hematuria via morning administration, frequent urination, hydration)
Used for: breast cancer, non-hodgkin’s lymphoma, pediatric malignancy
Other drugs: chlorambucil, melphalan
How do the bis(chloroethyl)amines alkylate?
What drugs does this group include?
What is its functionality?
bis(chloroethyl)amines = cyclophosphamide, mechlorethamine (nirogen mustard), chlorambucil, melphalan
BIFUNCTIONAL
One of the chloromethyl groups binds to the DNA, relatively quickly, the other one binds = bifunctional (more potent than monofunctional)
Alkylation could occur on the same strand (intra) or opposite strands (inter) –> crosslinks –> DNA replication and other DNA functions are impiared
Cytotoxicity is directly proportional to the amount of links formed
Ifosfamide:
potency incomparison to other alkylating agents?
Isomer of what other important alkylating agent?
Ifosfamide is useful to use with what types of cancers? (2)
What is one of its toxicities? How could this be prevented?
What side effect is dose limiting? What are other side effects (4)
Ifosfamide is an isomer of cyclophosphamide
It is monfunction, and only 1/5 the potency of others in the bis-group
Useful in the treatment of sarcomas and testicular cancers that have failed other primary therapy
Dose limiting AE: myelosuppression
Other side effects: hematuria (administered with MESNA to prevent toxic effect on urothelium), N/V, hair loss and at large doses lethargy and confusion
What is the use of MESNA?
MESNA is a dimer in the blood and cells thus not activ, in urine, mesna is a monomer* and has the ability to bind metabolites of alkylating agents (acrolein, etc) –> prevents *urothelial damage and hematuria that can be seen with some chemotherapy agents such as w/the bis(chloroethyl)amides.
Useful for: ifosfamine, cyclophosphamide
