Chemotherapeutic Drugs Flashcards
4 main types of chemotherapeutic drugs
- DNA-alkylating agents
- Anti-metabolites
- Microtubule-disrupting agents
- Topoisomerase inhibitors
What phase of the cell cycle is targeted by…
a) anti-metabolites
b) microtubule-disrupting agents
a) Anti-metabolites target the S phase (interfere with nucleotide synthesis and DNA replication)
b) Microtubule-disrupting agents target the M phase (interfere with the spindle apparatus during cell division)
How do DNA-alkylating agents work?
- Directly damage the DNA
- Add alkyl, methyl or ethyl groups to the DNA, causing the DNA to cross-link
- Cross-linked DNA cannot replicate effectively
Name 2 DNA alkylating agents
Cyclophosphamide
Dacarbazine
How does cyclophosphamide (alkylating agent) work?
It is a pro-drug that attaches alkyl groups to guanine bases in DNA. This causes:
1. Cross-linking of DNA strands (covalently-bound strands cannot separate for replication)
2. Mismatched base-pairing (replication error)
3. Strand breaks (DNA is unstable, damaged)
All of this makes it hard for cancer cells to divide, eventually killing the.
Dacarbazine is an alkylating agent used to treat…
- cancer of the lymph system
- malignant melanoma (skin cancer)
Alkylating agents (cyclophosphamide and dacarbazine) can be toxic to…
Rapidly proliferating cells:
- hematopoietic system
- GI tract
- Gonads
How can certain patients become resistant to alkylating agents?
- Via increased inactivation of the drug by nucleophilic “trapping agents”
- Via increased DNA repair to offset the damage and replication errors
- Via decreased activation of the pro-drug (by down-regulating cytochrome P450)
Name 3 anti-metabolites
Methotrexate
5-fluorouracil
Cytarabine
How does methotrexate (anti-metabolite) work?
Methotrexate is very similar in structure to folic acid (it is a folate analog) but functions as an antagonist, inhibiting the enzyme dihydrofolate reductase. This disrupts folate metabolism and inhibits thymidilate synthase, so we can no longer produce thymidine. This interferes with DNA and RNA synthesis.
What specific enzyme does methotrexate inhibit?
Dihydrofolate reductase (which eventually leads to the inhibition of thymidylate synthase)
How do 5-fluorouracil work (anti-metabolite)?
- It is an analog of uracil (a pyrimidine) and can thus be incorporated into RNA, which messes up RNA processing and function
- 5-FU is also a thymidine analog and inhibits the activity of thymidylate synthase, preventing thymidine production.
How does cytarabine work?
Cytarabine modifies the sugar in nucleotides to disrupt DNA/RNA structure.
It competes with dCTP (a normal building block) and gets incorporated into the DNA. This causes DNA strand breaks and triggers apoptosis of the cancer cells.
Name 3 microtubule-disrupting agents
Vincristine
Vinblastine
Taxols
How does vincristine (MTB-disrupting agent) work?
It binds tubulin and terminates MTB assembly. This results in microtubule depolymerization and mitotic arrest (cell cannot divide).
How do taxols (MTB-disrupting agents) work?
The promote microtubule assembly and inhibit disassembly. Since microtubules must be dynamic for proper chromosome alignment and separation, stabilization halts mitosis (cell cannot divide).
Name 2 topoisomerase inhibitors
Daunorubicin
Bleomycin
How do topoisomerases work and what happens when they are inhibited.
Normally, topoisomerases help unwind DNA from its coiled state (which is necessary for DNA replication).
Inhibition of this process leads to DNA strand breaks and cell cycle arrest.
How do daunorubicin and bleomycin (topoisomerase inhibitor) work?
- Inhibits topoisomerase, causing DNA strand breaks
- Intercalates into DNA, disrupting replication and transcription
What is the principle behind targeted therapies for cancer?
To specifically target cancer cells, and not harm healthy normal tissues
What is the Philadelphia oncogene?
It is a BCR-ABL fusion gene that results from a translocation between chromosomes 9 and 22, which is common in patients with chronic myeloid leukemia (CML). It encodes a constitutively active kinase, which is a very potent oncogene.
How does the Gleevec (Imatinib) drug work?
Gleevec inhibits the overactive kinase encoded by the Philadelphia gene.
It does so by occupying the ATP-binding site, preventing ATP binding.
This leads to the death of all CML cells with this oncogene.
Mainstay drug for diffuse large B cell lymphoma and chronic lymphocytic leukemia (CLL)
Rituximab (anti-CD20)
How does rituximab work?
It targets CD20, a protein found on B cells. It is a monoclonal antibody and by binding CD20, it marks B cells for destruction. Destroys both normal and malignant B cells
