EXAM #2: ANTINEOPLASTIC AGENTS Flashcards
What are the three major cell cycle checkpoints?
G1/S
G2/M
Metaphase/Anaphase
What are the specific criteria necessary to proceed through the G1/S checkpoint?
1) Cell nutrition, size, and environment must be favorable for replication
2) DNA must be intact
This check ensures the cell is prepared for DNA replication and to enter S-phase.
What are the specific criteria necessary to proceed through the G2/M checkpoint?
DNA must be completely replicated
This is the checkpoint that ensures the cell is ready to enter mitosis.
What are the specific criteria necessary to proceed through the metaphase/anaphase checkpoint?
1) DNA intact must be intact
2) Chromosomes must be attached to the mitotic spindle
This check ensure that the cell is ready for chromatid separation and is prepared for cytokinesis.
What are the three mechanisms of oncogene formation?
First, an oncogene is a mutated form of a normal gene that supported cellular proliferation i.e. “proto-oncogenes”
1) Point mutations
2) Chromosomal translocation
3) Proto-oncogene duplication/ amplification
How can point mutations lead to the development of an oncogene?
- Change in an amino acid regulatory region in the proto-oncogene product
- Amino acid change that makes the proto-oncogene resistant to degradation
How do chromosomal translocations result in oncogenes? Give an example.
Chromosomal translocation that causes the fusion of two genes, the product of which is the “fusion gene”
E.g. “Philadelphia” chromosome (9 x 22) ABL and BCR in CML
What is a major oncogene that is found in roughly 30% of all cancers?
Ras
Ras in involved in cell signaling/ GPCR signaling; mutations leave Ras permanently turned on.
Define first order killing of cancer cells i.e. what is the cell kill hypothesis?
This is the chemotheraputic elimination of a FIXED percentage of cancer cells.
This is first order kinetics*
What are the four goals of cancer drug therapy?
1) Curative intent
2) Adjuvant therapy
3) Neoadjuvant therapy
4) Palliation
List the general characteristics of chemotheraputic drug therapy.
- Drugs are cytotoxic and only PARTIALLY selective
- Low TI
Thus, adverse effects are common.
What are the general mechanisms of resistance to chemotherapeutic agents?
1) Genetic instability
2) Drug efflux pumps/ mutated drug transporters
3) DNA damage repair
4) Cell death inhibition
5) Drug inactivation
- Up-regulation of enzymes that metabolize drugs
6) Drug target alteration
7) Epithelial-Mesenchymal Transition
What types of tumors are easiest to treat with chemotherapy?
Tumors that are RAPIDLY growing
Define curative intent.
Drug therapy is intended to CURE the disease
Define adjuvant therapy.
- Drug given AFTER primary treatment e.g. surgery
- Prevent recurrence
Define neoadjuvant therapy.
Drug given FIRST to SHRINK tumor, making it amenable to surgery
Define palliative therapy.
Therapy intended to relieve symptoms and improve quality of life.
Do most cancers follow the cell-kill hypothesis? Why or why not?
NO
B/c of the cytotoxicity of chemotherapeutic, it is not possible to dose patients in a manner necessary to achieve 1st order kill.
What is a drug efflux pump?
A cellular transporter than “pumps” drugs out
E.g. MDR-2
What is Epithelial- Mesenchymal Transition (EMT)?
- Cell loses adhesive properties and becomes motile
- Changes can also cause drug resistance
What are the three general cytotoxic mechanisms to kill cancer cells?
1) Perturb normal DNA replication
2) Perturb mitosis
3) Starve cells of amino acids
What are the three targeted mechanisms to kill cancer cells?
1) Perturb hormone and growth factor signaling
2) Inhibit blood supply to tumor e.g. VEGF
3) Target activating proteins
What are cell-cycle non-specific drugs?
DNA alkylating agents that kill cells in ANY stage
Preferentially kill replicating cells
What are the S-phase specific drugs?
DNA synthesis inhibitors