Anticancer Drugs Flashcards
What are the three most prevalent types of cancer for each sec (4 total)
Males:
Prostate
Lung
Colorectal
Females:
Breast
Lung
Colorectal
What are the two hallmarks of cancer at the cellular level (What is altered)
- Regulation of cell proliferation
- Regulation of cell differentiation
What are 3 of the 7 warning signs of cancer?
- Change in bowel/blader habits
- A sore that does not heal
- Unusual bleeding or discharge
- Thickening or a lump in breast/elsewhere
- Indigestion or difficulty swallowing
- obvious change in a wart or mole
- Nagging cough or hoarseness
How is cancer cell growth described? (What does the graph look like)
Exponential growth over time (as opposed to gompertzian/sigmoidal)
True/False? Clinical detection of tumors is possible earlier on
False, happens after sigmoidal curve levels off
Name 6 ways to treat cancer cells
- Destroy neoplastic cells (with radiation/drugs/host immunodefenses)
- Removal via surgery
- Prevent metastases
- Convert tumor cells to normal cells
- Halt neoplastic cell division
- Block angiogenesis
What are the 3 principles of “classical” cancer chemotherapy?
- Cure = death of every malignant cell
- Do not rely on host mechanisms to eliminate moderate amounts of cancer cells
- Cell-kill follows first order kinetics (constant proportion)
True/False? The relationship between drug concentration and survival of cells is linear.
True
How do basic anticancer drugs kill tumor cells? (4 ways)
- Antimetabolits (Substitute/inhibit synthesis)
- Intercalation, damage, or alteration of DNA structure
- Inhibition of DNA transcription/translation
- Block of protein function within cells or on cell surface
Name 3 types of anticancer drugs
Alkylating agents
Anti-metabolites
Anti-tumor antibiotics
Name 2 alkylating agents used as anticancer drugs
Cyclophosphamide
Cisplatin
Name 3 antimetabolites used as anticancer drugs
Methotrexate
5-Fluorouracil
Cytarabine
Name 3 of the 6 Anti-tumor antibiotics
Vincristine
Vinblastine
Taxol
Doxorubicin
Etoposide
Bleomycin
True/False? Non-cell cycle phase-specific drugs are more effective than cell cycle phase specific drugs?
True
What type of anticancer drug are nitrogen mustards?
Alkylating agents
What do alkylating agents do, and what is the effect of their action? (4 consequences)
They alkylate DNA at the N-7 position of Guanine, this leads to:
- Miscoding
- Depurination
- Strand Breaks
- Cross links
Which is more effective, Monofunctional alkylating agent or a bifunctional one?
Bifunctional (by a lot)
True/False? Cyclophosphamide is the drug that is formed from metabolic activation of a prodrug
False
Cyclophosphamide is the prodrug, the active drug is Phosphoramide mustard
How do platins such as cisplatin work to prevent tumor proliferation? 4 methods
- Monoadducts
- Interstrand crosslinks
- DNA-protein crosslinks
- Intrastrand crosslinks
What are consequences of platin use? 3 symptoms
Ototoxicity, nephrotoxicity, nausea/vomitting
What are three causes of resistance to alkylating agents?
- increased inactivation (nucleophilic “trapping agents”
- Increased DNA repair
- Decreased activation
What are four main targets of alkylating agent toxicity?
(rapidly proliferating cells) - hematopoietic system - GI tract - Gonads May be associated with secondary malignancies
What is methotrexate an analog of?
Folic acid
What is the main action of methotrexate?
Inhibition of dihydrofolate reductase
What does a lower IC50 mean?
The drug is more effective at inhibiting its target
What metabolic pathway does methotrexate interrupt, and what can rescue this pathway?
Thymidylate synthase (starves cell of thymidine) Rescued by leucovorin
How does methotrexate need to be modified before it can alter the FH2 -> FH4 pathway?
It has to be polyglutamated
What are 2 mechanisms of methotrexate resistance
Impaired transport into cells
Impaired polyglutamate formation
What is 5-Fluorouracil an analog of?
Pyrimidine
What is the main action of 5-Fluorouracil?
Inhibition of Thymidylate synthase
Why are Methotrexate and 5-fluorouracil given together?
To shut down folate synthesis
What does Cytarabine do and how?
Inhibits DNA polymerase
Incorporated into DNA - terminates chain
What are 4 symptoms of antimetabolite resistance?
Changes in target enzymes
Decreased activation
Increased inactivation
Decreased access to target site
What are two classes of drugs that target microtubules?
Vinca alkaloids and taxanes
Name two vinca alkaloids
Vincristine
Vinblastine
Name a taxane
Paclitaxel
What are the main toxic effects of each vinca alkyloid?
Vincristine - neurotoxicity
Vinblastine - myelosuppression
What do vinca alkyloids do to microtubules?
block polymerization of MT, continues disassembly
What does Paclitaxel do to microtubules
Stabilizes polymerization
What is Abraxane?
Paclitaxel in albumin-coated nanoparticles
How do topoisomerase inhibitors function?
They inhibit topoisomerase II
Intercalate DNA, blocking DNA and RNA synthesis
Alter cell membrane fluidity and ion transport, generate free radicals
What cell cycle stage to topoisomerase inhibitors function at?
S-G2
Name a topoisomerase inhibitor
Bleomycin
Why do current drug regimes fail?
Drug toxicity
Drug resistance
Name 6 mechanisms of drug resistance
- DNA-Synthesis gene overexpression
- Altered target molecules
- Enzymatic deactivation
- Altered membrane transport - drug efflux
- Enhanced DNA repair
- Resisting drug induced cell cycle arrest/apoptosis
What are the 4 conditions for drugs during combination chemotherapy?
Each drug should be:
- Effective on its own
- Synergistic
- Have non-cumulative toxicities
- Given in maximum tolerated doses
What are three hormonal manipulations to treat cancer?
Glucocorticoid action
Block estrogen action
Block androgen action
Name a glucocorticoid receptor agonist
Prednisone
What are the effects of prednisone?
Triggers apoptosis, antilymphocytic effects
What is tamoxifen and what does it do?
Competitive partial agonist/antagonist at estrogen receptors
Suppresses IGF-1 and upregulates TGF-beta
What does anastrozole do and what is a consequence of its action?
Blocks aromatase (test - estradiol), blocks synthesis of estrogen from androgens
How does ER+ cancer cell growth differ in pre and post menopausal women?
Post-menopausal women do not have active aromatase in the body, less estrogen in circulation therefore less estrogen reaches cancer cells, growth stunted
What does Flutamide do?
Blocks androgen action at the receptor level
blocks interactions between co-activators and other factors
What enzyme does Finasteride block and what is a consequence of this?
5-alpha reductase (testosterone -> dihydrotestosterone)
DHT production stopped
True/False? Gonadotropin-releasing hormone agonists/antagonists can induce hypogonadism as well as suppress gonadotropin release
True
What is L-asparaginase? When is it used? Why?
An enzyme given as a drug, converts Asparagine into aspartic acid.
Used in Acute lymphoblastic leukemia:
Tumor cells lack asparagine synthetase; L-asparaginase depletes the L-asparagine in the cells, prohibiting protein synthesis
Name a cancer specific enzyme and the drug that targets it
Fused BRC-ABl (cancer specific tyrosine kinase) formed by translocation of chormosomes
Imatinib will inhibit this enzyme, preventing rapid proliferation but LEAVING THE CELL ALIVE
True/False? Antibodies against specific growth factor receptors only bind to the receptor
False, can bind the ligand as well
What does Trastuzumab target?
Human epidermal groowth factor receptor, HER2
Why are solid tumors harder to treat?
Secrete factors that trigger angiogenesis
What is Bevacizumab and what does it target?
VEGF-A (angiogenesis marker)
What does Pembrolizumab target?
PD-1 (program death receptor)
Normally PD-L1 binds PD-1 and prevents death of tumor cell
How does Brentuximab vedotin work?
Antibody-drug conjugate:
Antibody loaded with cytotoxic payload
Payload is removed once endocytosed (most likely by tumor cell)
How can retinoic acid be used as an anticancer drug and what is a potential side effect?
Promotes terminal differentiation of leukemic promyelocytes
Teratogenic
What is PARP?
Poly ADP Ribose Polymerase, involved with detection of DNA damage. Normally binds ds breaks and catalyses repair
What is Olaparib?
PARP inhibitor, alters DNA damage detection pathway
If BRCA1/2 is mutated (e.g. in breast cancer) No homologous repair can happen and the cell dies
If cell is healthy, homologous recombination occurs and cell lives
What is immunomodulation? give an example
Anticancer vaccine. eg interferon alpha
What does Interferon Alpha do?
decreases cell proliferation and inhances immune activities
Name a cancer treatment vaccine
Sipuleucel-T (neat and expensive!)
What are the 4 steps in chimeric antigen receptor T-cells?
1) T cell collection
2) T cell transfection
3) T cell adoptive transfer
4) patient monitoring
eg Axicabtagene ciloleucel
What are oncomirs and what do they do?
Proliferate cancer growth
Name 4 oncomir inhibitors
miRNA sponges
Anti-miR oligos (AMOs)
Small molecule inhibots
miRNA masks/target protectors
Name 2 anti-oncomirs
miRNA mimic
gene therapy
What do miRNAs and anticancer drugs both promote?
Apoptosis
What are the methods of treatment for Breast cancer in the case of: ER Positive (2 methods) and ER Negative (4 methods)?
ER+: - Aromatase inhibitors (after menopause) - Anti-estrogens: tamoxifen ER-: - Doxorubicin - Docetaxel - Cyclophosphamide - Trastuzumab (HER-2+)
What are 3 drug treatments for prostate cancer?
Hormonal therapy for metastases: -Testosterone reduction: LHRH agonist plus androgen antagonist Combination chemotherapy - Docetaxel - Prednisone Hormone Refractory Prostate Cancer: - Sipuleucel-T
Three treatments for Gliobastoma?
Tumor resection
Radiotherapy
Temozolomide
IL13Ralpha2-targeted CAR-T cells(?)
