Cancer Pharm: Alkylating Agents Flashcards
Major MOA of alkylating agents and causes arrest where in cell cycle?
- Transfer of alkyl group to DNA –> DNA cross-linking
- Arrest occurs in late G1, early S phase
What are 3 mechanisms to resistance of Alkylating agents?
- ↑ capability to repair DNA lesion –> ↑ expression MGMT
- ↓ cellular transport of the alkylating drug
- ↑ expression of glutathione
What is the most widely used alkylating agent that has a high oral bioavailability and can be given IV?
Cyclophosphamide
Which intermediate of Cyclophosphamide is further broken down into products that have cytotoxic effects on tumor cells; what are these products?
Aldophosphamide —> Phosphoramide mustard + Acrolein
Which toxic metabolite of Cyclophosphamide is responsible for the antitumor effects?
Phosphoramide mustard
Which toxic metabolite of Cyclophosphamide is associated with hemorrhagic cystitis?
Acrolein
What should patients receive when on high doses of Cyclophosphamide?
Vigorous IV hydration
Complete remissions and presumed cures have been seen with Cyclophosphamide when given as a single agent for what type of cancer?
Burkitt Lymphoma
Which alkylating agent has been used topically for tx of cutaneous T-cell lymphoma; why has it been largely replaced?
- Mechlorethamine
- Most reactive drug in the class; more stable drugs exist
Which alkylating agent causes less N/V and alopecia compared to other drugs in this class; toxicity of this drug is mostly of what kind?
- Melphalan
- Toxicity is mostly hematological
Major dose-dependent AE of the alkylating agent, Chlorambucil?
- Well tolerated in small daily doses
- Large oral doses can cause N/V (>20mg)
What is the clinical use for the alkylating agent, Chlorambucil?
- Chronic Lymphoblastic Leukemia
****ChLorambuciL (CLL)****
Which 2 alkylating agents are lipid soluble nitrosoureas allowing them to cross BBB and be effective in treating brain tumors?
- Carmustine and Streptozocin
- Generate both alkylating and carbamylating moieties
What is the major action of the alkylating nitrosourea, Carmustine; how can resistance develop?
- Alkylation of DNA
- This can be repaired by MGMT
What are the AE’s of the nitrosourea, Carmustine; which AE’s arise with high doses?
- Profound and delayed myelosuppression: recovery 4-6 weeks after a single dose
- High doses w/ bone marrow rescue, produces hepatic VOD, pulm. fibrosis, renal failure, and 2’ leukemia
What is the clinical use of Carmustine and what makes this drug so effective in these tumors?
- Malignant Glimoas (implantable Carmustine wafer)
- Methylation of the MGMT promter inhibits MGMT expression in 30% of primary gliomas
- Assoc. w/ sensitivity to carmustine and other nitrosureas
The nitrosourea, Streptozocin, has a high affinity for what cells?
Cells of the islets of the Langerhans in the pancreas
What are some of the frequent and serious AE’s associated with Streptozocin?
- Frequent nausea
- Mild reversible renal or hepatic toxicity occurs in ~2/3 of cases
- 10% will have cumulative dose renal toxicity CAN lead to renal failure