Flashcards in topic 7 Deck (32):
How do tumor cells arise? What causes heterogeneity in a tumor?
Tumor cells arise from a single cell with a specific genetic defect.
They have a lot of genetic instability leading to lots of mutations. They also have distinct microenvironments depending on where they are in a tumor or in the body which enhances this heterogeneity.
What is the main goal of chemotherapy?
What are 2 sub goals to accomplish it?
Give the patient a normal life expectancy. To do so, you use drugs which:
Have selective toxicity b/w tumor and normal cells (tough b/c only subtle differences exist)
Kill all malignant cells b/c one is enough to grow the tumor back.
What kind of cells are targeted by many chemotherapeutic agents? How does this affect BM?
Most drugs target rapidly dividing cells b/c that's what tumors do. However, that means they also target normals cells that regularly divide. suppression of bone marrow function is usually the dose limiting factor with chemotherapeutic agents
How is hormone dependence used in anti tumor drugs?
Some tumor cells are hormone dependent. If the source or effect of the tumor is blocked, tumor regression can happen.
What is a tumor's growth fraction? Why is it important with anti-tumor drugs.
A Low growth fraction means that not many cells are dividing. Tumors with a high growth fraction are more susceptible to chemotherapeutic agents. Also, by making a tumor small through surgery or radiation, you can often induce the tumor cells to start dividing so chemo can work.
What is the log kill hypothesis? How can you achieve maximum killing?
A repetition f a constant high dose of drug kills a constant percent of cells with each dose.
N-killed=N-total x K, where K is a constant that depends on the dose.
Max kill is achieved by using high doses over the shortest possible intervals
What are the two overall types of drug resistance used by tumors.
Natural resistance: Tumor cell naturally blocks cytotoxic effects of drugs
Acquired or selected resistance: Mutations (1 every 10^5 or 10^6 cell divisions) occur which make a cell more resistant. Other cells die and the more resistant cells repopulate.
What are 3 reasons why multiple drugs should be used?
Resistance develops rapidly to a single drug
Heterogeneity of tumor cells. Different cells will respond to different drugs.
Each drug independently gives log kill (can combine them)
What are 4 guidelines for picking which drugs to use together?
Use drugs that are effective alone
Use drugs that have different mechanisms of action
Use drugs whose toxicity overlaps as little as possible
Use drugs that are compatible wth patients age and health status (infertility, etc.)
What is adjuvant therapy?
Treatment to block recurrence of cancer following removal of tumor by surgery or radiation treatment (Continually Give a drug to prevent relapse).
What are two types of DNA damaging agents?
Crosslinking agents and DNA cleaving drugs
What are two types of cross linking agents? How do cross linking agents work? What is an example of each? What are these drugs general characteristics?
They damage DNA by covalently binding to DNA causing cross linking of strands which prevents transcription and duplication.
Cyclophosphamide (Nitrogen mustard). Activated by P450 enzymes, major toxicity is bone marrow suppression.
Cisplatin (platinum analogs). Renal toxicity
What are two examples of DNA cleaving drugs? How do they function? What is their major toxicity?
Bleomycin: Binds to DNA backbone and cleaves it through radicals. Pulmonary toxicity. Lacks BM toxicity.
Doxorubicin: Produces O2 free radicals which cleave DNA. Major toxicity: BM suppression and cardiac toxicity-->Congestive heart failure
How do antimetabolites work in general? What are 3 types of Antimetabolites? How does each work? What is an example of each one?
They are structural analogs of naturally occurring metabolites that interfere with metabolic pathways. Folic acid analogs, pyrimidine, purine analogs.
How do folic acid analogs work? Give an example of one drug, how it works, and its major toxicity.
Folic Acid analogs: Rapidly dividing tumor cells use lots of folic acid to get nucleic and amino acids
Methotrexate: Folic acid analog that works by competitive inhibition on DHFR, which coverts FH2 to FH4. When this happens, there is a pyrimidine shortage, a purine shortage, and glycine and methionine can't be synthesized as well. All this leads to cell death.
Major toxicity: BM suppresion (leukopenia and thrombocytopenia).
How do pyrimidine analogs work? Give an example of one drug, how it works, and its major toxicity.
Fluorouracil (5-FU)-Flourinated uracil derivative; some tumors rapidly convert uracil into thymidine for incorporation in DNA/RNA. In RNA-->can't form full size ribosome. In DNA-->strand breaks. Also, a metabolite, FdUMP makes it so you can't convert dUMP to dTMP leading to an imbalance of NTs and a DNA cleaving endonuclease.
Major toxicity:BM suppression
How do purine analogs work? Give an example of one drug, how it works, and its major toxicity.
Mercaptopurine: Causes feedback inhibition of first step in purine biosynth pathway which leads to less purines. Causes DNA strand breaks and Inhibition of RNA synth.
Major toxicity: BM Suppression
How do mitosis inhibitors work? What is an example; how does it work and what is its major toxicity?
They bind to tubulin and alter normal formation of microtubulin and mitotic spindle.
Paclitaxel (taxol)-M phase specific; stabilizes microtubule formation-->arest in G2 or mitosis.
Major toxicity: neutropenia
How can hormones be used to treat breast cancer? What are 3 classes of drugs
50% of individuals with breast cnacer have tumor cells bearing the estrogen receptor (ER+) meaning that they need estrogen to grow. These can be treated with endocrine therapy. Those whose tumor cells are ER- need classical chemo.
Selective estrogen receptor modulators (SERMs), Aromatase Inhibitors (AI), Selective estrogen down regulators (SERDs).
How do selectiv estrogen receptor modulators (SERMs) work? What is an example? What are its affects on tumors, BM, and uterus? How are premenopausal and post menopausal women affected differently? Where is it activated?
They bind to ER and have estrogenic or antiestrogenic effects depending on the tissue.
Tamoxifen-It converts the estrogen receptor to a partially active form. In breasts (the tumor), corepressors make the receptor inactive (stops tumor growth). In bone/uterus, coactivators make it active (increased bone density). In the post-meno patients, the pro-growth effects in the uterus leads to an increased incidence of endometrial cancer. This is not observed in pre-meno patients.
It is activated by P450, which means a mutation in P450 could make it not work for some patients.
How do Aromatase inhibitors works? What is an example?
Lower estrogen levels by inhibiting aromatase which is necessary for the synth of estrogen.
Letrozole. It is used in adjuvant therapy in post meno and in advanced metastatic breast cancer in post meno patients. They are not effective with pre-meno patients.
How do SERDs work? An example?
Selective estrogen receptor down regulators bind the ER and induce its down regulation.
Fulvestrant can be used to treat ER+ post meno women who no longer respond to tamoxifen or letrozole.
How are hormones used to treat prostate cancer?
Most prostate cancers rely on androgens for growth and by taking away androgens, tumors usually regress.
What are 2 examples of drugs used to treat prostate cancer by anti-adrenergic means that are often used together? What is CAB?
Leuprolide-GnRH superagonist that binds and downregulates the GnRH receptor which leads to less androgen secretion by testes. However, it does not affect the small amt. of androgens released by the adrenal gland. Other drugs are needed to do that.
Flutamide-AR antagonist that blocks androgens from binding to AR. It is not effective when used alone b/c it leads to more FSH and LH being secreted. Therefore, it is used with leuprolide b/c it will block that secretion. Using both together is referred to as complete androgen blockade (CAB)
What is abiraterone? How does it work? What are some adverse affects and how do they come about?
It inhibits CYP17 and thus blocks androgen biosynth at testes, androgen glands, and prostate tumor tissue.
It can leads to adrenocoritcal insufficiency which can cause hypertension, hypokalemia, and fluid reterntion. Basically decreased cortisol leads to increased ACTH from the pituatary which leads to increased aldosterone which leads to increased sodium (hypertension), increased fluid retention, and decreased potassium (hypokalemia). To prevent this, cortisol should be given with the drug.
How are corticosteroids used to treat cancer? which cancers are treated? What is an example?
In lymphoid tissues, high doses of glucocorticoids induce cell death. They bind the glucocorticoid receptor which leads to caspases then apoptosis. Therefore, they can be used to treat lymphatic anemias, Hodgkin's disease, and non-hodgkins lymphoma.
They are no BM suppressors
Prednisone is a synthetic glucocorticoid and is thought to upregulate pro-apoptosis genes.
It can lead to decreased glucose tolerance (increased glucose levels b/c receptors won't take it) and acute tumor lysis syndrome (result of too much lysis of tumor and dumping of contents into solution.
What are 4 examples of targeted approaches to chemotherapy?
Monoclonal antibodies, tyrosine kinase inhibitors, Proteasome inhibitors, and Histone deacytlase inhibitors
What are 2 examples of monolconal antibodies?
Trastuzumab (herceptin)-25-30% of breast cancer tumor cells have the epidermal growth factor receptor type 2. Herceptin binds to the receptor and blocks binding of EGF. Small percentage of peole get heart failure.
Bevacizumab (Avastin)-many tumor cells secrete VEGF which leads to angiogenesis. Avastin binds to the VEGF receptor and blocks binding of VEGF. Many patients require treatment for hypertension while on drug. It can also cause bleeding.
What are two examples of Tyrosine Kinase inhibitors?
Imatinib (gleevec)-Specific inhibitor of BCR-ABL. It binds to the intracellular ATP binding site and blocks catalytic activity. It is given orally and may be taken with food or fluids.
Lapatinib (TYKERB)-Inhibitor of epidermal growth factor receptors type 1 and 2. Binds to intracellular ATP binding site and blocks catalytic activity. Associated with decrease in left ventricular ejection fraction.
What is an example of a proteasome inhibitor?
Bortezomib (velcade)-inhibitor of 26S proteasome-used to treat Multiple myeloma
What is an example of a histone deacetylase inhibitor?
Vorinostat (Zolina) inhibits histone deacetylases causing an accumulation of acetylated histones that are transcripted at inappropriate times lead to cell cycle arrest or apoptosis.