Cancer and Carcinogens Flashcards
What re the 3 stages of neoplastic development? How does it progress from each stage to the next?
- Neoplastic cell (growth/promotion) - Differentiated neoplastic cell (progression) - Undifferentiated cancer
What are the 4 properties of chemical carcinogens?
- Carcinogenesis is dose dependent
- Long lag periods between exposure and appearance of tumors (> 20 years in humans)
- Carcinogens are subject to activation and degradation
- Active carcinogens are electrophiles
What is an active carcinogen called?
Pro-carcinogens
What were the findings of the Mega Mouse experiment?
- Mice were given a carcinogen at very low levels
- Kidney cancer developed linearly
- Bladder cancer had no response
- Some cancers respond linearly to carcinogen exposure
- Some do not develop at all at low levels
How many different well established human chemical carcinogens have been discovered?
More than 20
What are 9 examples of human chemical carcingens?
- Aflatoxins
- Benzopyrene
- Benzene
- Conjugated estrogens
- Cyclophosphamide
- Mechlorethylamine
- Phenacetin
- TCDD
- Vinyl chloride
What carcinogen develops in moldy food stuffs?
Aflatoxins
What carcinogen is a nitrogen mustard/ nerve gas?
Mechlorethylamine
What human chemical carcinogen is the most potent?
Aflatoxins
What human chemical carcinogen is a product of combustion?
Benzopyrene
What human chemical carcinogen is an immunosuppressant?
Benzene
What 2 human chemical carcinogens are alkylating agents?
- Cyclophosphamide
- Mechlorethylamine
What human carcinogen results from DES exposure?
Cyclophosphamide
What human chemical carcinogen is a coal tar derivative?
Phenacetin
What human carcinogen is used to make PVC plastic?
Vinyl chloride
What human carcinogen is dioxin?
TCDD
How do direct acting carcinogens work?
Mechlorethylamide or another electrophile attach to reactive sites on DNA, altering genes
What activates carcinogens into procarcinogens?
Cytochrome P450
What are 3 types of epigenic carcinogens?
- Immunosuppresors (Benzene)
- Hormones (DES)
- Solid-state carcinogens (Asbestos)
What are oncogenes?
Genes taht encode for transforming proteins that can cause cancer
What do oncogenes develop from?
Proto-oncogenes (genes in normal cells that encode for proteins involved in cellular regulation)
What are proteins involved in cell regulation?
- G proteins
- Tyrosine-specific kinases
- Other protein kinases
- Growth factors
- Transcription regulators
What are anti-oncogenes?
Tumor suppressor genes
What stages of cell point do cells normally go through “checkpoints?
- G1
- G2
- Metaphase
What are the oncogenes involved in breast cancer?
- BRCA1
- BRCA2
What are 5 childhood tumors with high cure rates? What do they have in common?
- Acute lymphocytic leukemia
- Burkitt’s lymphoma
- Ewing’s sarcoma - bone tumor
- Retinoblastoma
- Wilms’ tumor - kidney tumor
All fast growing
What are 5 adult tumors with high cure rates?
- Hodgkin’s disease
- Non-Hodgkin’s lymphomas
- Trophovlastic choriocarcinoma
- Testicular germ cell cancer
- Ovarian germ cell cancer
How does chemotherapy work?
- Inhibits cell proliferation
- Cancer cells are rapidly proliferating, and are especially sensitive
What non-cancer cells are affected by chemo?
- Bone marrow
- Hair
- GI
- Oral mucosa
- Other rapidly dividing cells
What drug is used to increase WBCs in combination with chemo?
- Filgrastim (Neupogen)
Why do patients often experience nausea during chemotherapy?
- Chemical trigger zone is one of only areas without blood brain barrier, and is sensitive to the drug
What drug can be used to prevent the nausea associated with chemo?
Ondansetron (Zofran)
What causes resistance to chemotherapy?
Cancer cells divide fast, and adapt to the drugs. The most common mechanism is P-glycoprotein that pumps the toxins of the chemotherapy out of the tumor
How can multiple agents be used in chemotherapy?
Use drugs that different different parts of the cell cycle
What is the ABVD regimine therapy for Lymphoma-Hodgkin’s?
- Doxorubicin
- Bleomycin
- Vinblastine
- Dacarbazine
What type of drugs generally work in the DNA synthesis portion of the cell cycle?
Anti-metabolites
What is growth fraction?
Proportion of cells actively profliterating
What are the grow characteristics of tumors?
- Grows rapidly initially
- Slows because it can’t support its own growth due to hypoxia, poor nutrient supply, immunological defenses
What is the log kill hypothesis?
Chemotherapy reduces the tumors to a level at which the body’s immunological responses can take over and completely eliminate the cancer
What is the MOA of alkylating agents?
- Transfer alkyl groups to DNA, inhibiting cell division
What portion of the cell cycle do alkylating agents affect?
Non-specific
What are 3 adverse effects of alkylating agents?
- Bone marrow suppression
- Nausea
- Vomiting
Why must alkylating agents be administered via IV?
They have vesicant properties, meaning outside of the blood vessel, it can cause tissue damage and necrosis
What are 2 examples of alkylating agents?
- Mechlorethamine (mustargen)
- Ifosfamide (lfex)
Why can Ifosfamide be taken orally even though it is an alkylating agent?
It is activated by the body
What is the MOA of platinum coordination compounds?
Similar to alkylating agents
- Use meta complexes
What are 2 examples of platinum coordination compounds? What do they target?
- Cisplatin (testies, lymph tissue, ovaries)
- Carboplatin (paraplatin) (ovarian cancers)
What is an adverse effect of platinum coordination compounds?
Kidney toxicity
What is the MOA of antimetabolites?
Inhibit metabolic steps required for DNA synthesis
What phase of the cell cycle do antimetabolites act on?
S phase
What are 5 adverse effects of antimetabolites?
- Immunosuppresant
- GI lesions
- Alopecia
- Bone marrow depression
- Skin rash
What other conditions may antimetabolites be used to treat?
Autoimmune diseases such as RA
What antimetabolite targets folic acid?
Methotrexate
What antimetabolite targets purine synthesis?
Mercaptopurine
What antimetabolite targets pyrimidine synthesis?
Fluorouracil
What plant are vinca alkaloids derived from?
Periwinkle plant
What phase of the cell cycle do vinca alkaloids act on?
M phase
What types of cancer are vinca alkaloids use din?
- Breast cancer
- Choriocarcinoma
What are 4 adverse effects of vinca alkaloids?
- Bone marrow suppresion
- Alopecia
- GI lesions
- Neurotoxicity
What are 2 vinca alkaloids?
- Vincristine
- Vinblastine
What is the MOA of cytotoxic antibiotics and synthetics?
- Bind to DNA to inhibit RNA synthesis
What cell phase do cytotoxic antibiotics and synthetics act on?
G2 phase
What are adverse effects of cytotoxic antibiotics and synthetics?
- Visual toxicity
- Unique, drug-specific side effects
What antibiotic/ synthetic drug is used to treat lung fibrosis?
Bleomycin
What is an example of anti-estrogen drug? What is it used for?
- Tamoxifen
- Treats breast cancer
What are other TYPES of hormonal drug therapies?
- Androgens for breast cancer
- Anti-androgens for prostatic cancer
- Progestins for advanced breast cancer or endometrial carcinomas
What drugs block cancer cell signaling?
- Tyrosine Kinase Inhibitors
- Monoclonal Antibodies
- Cox-2 inhibitors
- Thalidomide
What signals do Tyrosine Kinase Receptors transduce?
- Growth
- Division
- Migration
- Synthesis
- Apotosis
What type of protein are Tyrosine Kinases?
An enzyme
What does Tyrosine Kinase act on? What do they do?
Phosphorylates tyrosine residues
What cells do tyrosine kinase receptors become active in?
Cancer cells
What are some major TKR families?
- Epidermal growth factor receptor & family
- Vascular endothelial growth factor receptor & family
- Insulin receptor and family
- etc…
What types of cancer demonstrate high epidermal growth factor receptor expression?
- NSCLC
- Prostate
- Gastric
- Breast
- Colorectal
- Pancreatic
- Ovarian
What is high expression of EGFR associated with?
- Invasion
- Metastasis
- Late-stage disease
- Chemotherapy resistance
- Hormone-therapy resistance
- Poor outcome
What is VEGFR increased in patients with growing tumors?
Large tumors require blood vessels to grow instead of relying on diffusion from nearby blood vessels.
- Tumors release VEGF to stimulate growth of new vessels into the tumor
How large can a tumor grow without a blood supply?
1 - 2 mm^3
What is angiogenesis?
Growth of new blood vessels
Do tyrosine kinase inhibitors act inside or outside of the cell?
Inside
What is a tyrosine kinase inhibitor that is specific to Bcr-Ab which is active in CMLl?
Gleevec
What organ does tyrosine kinase inhibitors adversely affect?
Skin
What is CML?
Chromosomal rearrangement that fuses two genes together.
- Produces oncogene, which encodes a form of tyrosine kinase (BCR-ABL)
What type of TKR inhibitor can act outside of the cell?
Monoclonal antibodies
What monoclonal antibody targets breast cancer?
Herceptin (Trastuzumab)
What monoclonal antibody is the only one that targets blood vessels?
Avastin (Bevacizumab)
What type of cancer is Avastin used to treat?
- Colorectal carcinoma
What are 3 adverse effects of Herceptin?
- Cardiomyopathy
- Anemia/ leukopenia
- Rashes
What are 4 adverse effects of Avastin?
- Thrombosis
- Hypertension
- Proteinuria
- Bleeding
How does Cox-2 facilitate tumor development?
Cancer cells overexpress Cox-2, causing an expression of VEGF through production of PGE2
How is Cox-2 treated?
- Cox-2 inhibitors downregulate angiogenesis causing factors such as VEGF
What does Thalidomide block angiogensis?
- Blocks VEGF through a decrease in the cell’s ability to induce COX2 expression
What type of cancer is Thalidomide best suited towards treated?
Multiple Myeloma (plasma cell disorder)
What is the limitation of antiangiogenic therapy when compared with other chemotherapies?
- Inhibits tumor growth instead of regressing established tumors
What is the clinical value of antiangiogenic therapy?
- Prolongs acute conditions to chronic
- Gives individuals extra time (extra month)
