Antineoplastic Drugs I
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. What would you like to do?
What are the established treatments for cancer?
Surgery, Radiation therapy, Chemotherapy
What are the relatively new treatments for cancer?
Immunotherapy, Targeted therapy, Photodynamic therapy, Gene therapy
What are some characteristics of a benign tumor?
- grow slowly
- well defined capsule
- well differentiated (how well cancer cells resemble regular cells)
- low mitotic index
- non metastasizing
Characteristics of a malignant tumor?
- grow rapidly
- not encapsulated
- poorly differentiated
- high mitotic index
One of the first characteristics of a cancer cell is sustained proliferative signaling. Describe this process
Normally a growth factor would bind to a receptor and result in cell replication. In a cancer cell there is a mutation where this is signaling of a cell replication without the ligand.
This is described as a mutant gene that in their nonmutant state directs protein synthesis and cellular growth.
Oncogenes - "good guy turned bad"
What is a tumor suppressor gene?
- Encodes proteins that in their normal state negatively regulate proliferation.
- Also called anti-oncogenes
What is the term for a normal, nonmutant gene that codes for cellular growth?
T/F: One of the hallmarks of cancer cells is to evade growth suppressors.
What are the growth suppressors that are active in normal cells?
1) TP53 - receives inputs from stress and abnormality sensors from within the cell's intracellular operating systems and leads to apoptosis.
2) RB (retinoblastoma-associated protein) transduces growth inhibitory signals that originate largely outside of the cell. Stops cell from going to S phase.
What is the intrinsic protein that causes cell apoptosis normally?
P53. activated in a number of ways including chemotherapy and radiotherapy which cause DNA damage.
How do cancer cells enable replicative immortality?
- By activating telomerase.
- Telomeres are protective caps on each chromosome and usually become smaller and smaller with each cell divison. In cancer they somehow activate telomerase and limitations of mitosis are not a problem anymore.
True or False. Inducing Angiogenesis is a hallmark of cancer.
- Examples of activators include: VEGF-A, B, C, FGF1, FGF2
- Examples of inhibitors: thrombospondin 1,2, interferon alpha and beta, angiostatin, endostatin, collage IV fragments
How do cancer cells activate Invasion and Metastasis?
- 1) Localized invasion - the tumor is formed and grows slowly toward capillary
- 2) Intravasation - cancer cells fit through the endothelial lining of blood vessels and circulate throughout body
- 3) Extravasation - while circulating it fits through the endothelial lining of blood vessels into sometype of organ/tissue
- 4) Formation of micrometastasis
- 5) Colonization - formation of macrometastasis
True or False. All cancers have a certain amount of inheritability.
False. Only some cancers are inheritable.
Name some internal factors that cause the formation of cancer cells.
- Point mutations
- chromosome translocations
- gene amplification
- mutation of tumor-suppressor genes
- loss of herozygosity
- gene silencing
- chromosome instability
- Epigenetic changes - DNA regulation change, NOT sequence change. ex: histone defect
How does inflammation (external factor) play a role in causing the formation of cancer cells.
- 1) Inflammation
- -Cytokine release from inflammatory cells.
- -Free radicals
- -Promotion of mutations
- -Decreased response to DNA damage
What are some external causes (other than inflammation) of cancer formation?
- 1) Chemicals : carcinogen
- 2) Viruses: Hep. B & C, Epstein-Barr virus, Kaposi sarcoma herpesvirus, HPV, Human T-cell leukemia-lymphoma virus
- 3) Bacteria: Helicobacter pylori4) Ionizing radiation, UV radiation, Electromagnetic fields, Cancer treatment
Explain the cell phase cycle. (M, G0, G1, S, G2)
- M phase is mitosis which includes the prophase, metaphase, anaphase and telophase.
- G0 phase is the resting phase in terms of cell growth.
- G1, S and G2 phase is collectively known as Interphase
- G1 phase is a period where cells are responsive to mitogenic GF's and TGF-beta. Entrance into S phase is blocked if there is any DNA damage
- S phase is a period where DNA synthesis occurs. DNA replication is halted if the genome is damaged
- G2 phase period where microtubules are formed before the M phase. Entrance into M phase blocked if DNA replication is incomplete.
What is the log-kill hypothesis?
The suggestion that a fraction of cancer cells always rest in G0 phase and therefore are NOT sensitive to chemotherapy.
True or False. Tumor cells can be killed after one or two treatments of chemotherapy.
False. Refer to log-kill hypothesis. It takes many cycles to kill all the tumor cells. May take many years.
True or False. Chemotherapuetics kills both cancer and healthy cells
What healthy cells are considered fast dividing cells and therefore are susceptible to chemotherapy?
Bone marrow, GI, and hair follicle cells
List some general toxicities of chemotherapy.
- Hair loss
True or False. Combination chemotherapy is used with drugs that have different mechanisms of action.
Why is combination chemotherapy used?
- It decreases chance of resistance to chemo drugs.
- Aim for maximal cytotoxicity with tolerated host toxicity
What are some ways cancer cells can resist chemo drugs?
- 1.Reduced drug uptake
- 2. Enhanced EGFR/MAPK/ERK signaling --> enhances proliferation
- 3. Inhibition of apoptosis
- 4. Changes in drug-target interaction
- 5. Enhanced drug inactivation
- 6. Reduced drug activation
- 7. Enhanced drug export
What are the rules for combination therapy?
- -Efficacy: only drugs known to be somewhat effective against same tumor when used alone
- -Toxicity: Drugs with little overlapping toxicity. Broadens ADRs but improves tolerance of single organ/system
- -Optimum scheduling: drug combos should be given at consistent intervals for recovery
- -Mechanism: synergistic effect whenever possible. different MOA
- -Avoid arbitrary dose changes
True or False. Most chemotherapy drugs target the DNA somehow.
What would you like to do?
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