Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
126 Cards in this Set
- Front
- Back
|
What cells are targeted by chemotherapy drugs? |
Dividing cells |
|
|
S phase fraction (Definition) |
The percentage of cells currently in the S phase of the cell cycle |
|
|
What is the relationship between S phase fraction and tumor severity? |
High S phase fraction is one of the primary clinical indices of tumor severity |
|
|
What is considered a high S phase fraction? |
~35% |
|
|
Can a cell return to G₁ after entering S phase? |
No |
|
|
What happens in the cell during S phase? |
Synthesis of nucleotides
Initiation of origins of replication
DNA replication |
|
|
What happens when S phase is interrupted? |
Apoptosis |
|
|
What happens during M phase? |
Chromatin condenses
Chromosomes align
Nuclear envelope breaks down
Spindle apparatus forms
Cell divides |
|
|
Most adult human cells are in what phase of the cell cycle? |
G₁ |
|
|
For some localized cancers, ____ can essentially cure the cancer |
Surgery |
|
|
For some metastatic cancers, ____ kills disseminated tumors and can cure the disease |
Chemotherapy |
|
|
What is the goal of therapy for patients with types of cancer that cannot be cured? |
Limit tumor growth
Improve quality of life |
|
|
Why does chemotherapy affect both cancerous and non-cancerous tissues? |
Some of the non-cancerous cells of the body are dividing (e.g. hepatocytes, gut epithelium, blood cells, etc.) |
|
|
What are the main side effects of chemotherapy drugs? |
Immune suppression
Nausea and vomiting |
|
|
Why are chemotherapy drugs with different targets often combined? |
To limit development of resistance |
|
|
What factors influence drug choice in chemotherapy? |
Tissue-specific drug uptake
S phase fraction in different tumor types
Ability of cells to undergo apoptosis |
|
|
What does it mean for chemotherapy to be applied in an adjuvant setting? |
In addition to surgery and radiation (potentially at the same time) |
|
|
Why is chemotherapy generally applied in an adjuvant setting? |
It helps kill micrometastases, which are a likely cause of cancer recurrence |
|
|
What type of drug is cisplatin? |
A platinum derivative |
|
|
What is the mechanism of cisplatin? |
Cross-linking DNA |
|
|
What is a major side effect of cisplatin? |
Renal toxicity |
|
|
How can the renal toxicity caused by cisplatin be suppressed? |
Hydration |
|
|
What type of drug is paclitaxel? |
An anti-mitotic drug |
|
|
What is the mechanism of action of paclitaxel? |
Promotes tubulin polymerization and blocks dissassembly, arresting cells in mitosis |
|
|
What drugs antagonize paclitaxel activity? |
Drugs that block entry into mitosis |
|
|
What are the major side effects of paclitaxel? |
Neuropathy (weakness, numbness, tingling)
Hypersensitivity (treated with antihistamines)
Arrhythmias |
|
|
Why does paclitaxel cause neuropathy? |
Microtubules are important in neuronal transport of neurotransmitters |
|
|
What happens to cells after a prolonged mitotic arrest? |
The cells continue to divide without a full set of chromosomes, eventually resulting in cell death |
|
|
How is paclitaxel metabolized, and why is it important? |
Paclitaxel is efficiently inactivated by CYPs, so drug interactions with P450 modifiers are likely |
|
|
What type of drug is doxorubicin? |
An antibiotic |
|
|
Where does doxorubicin come from? |
It is a product of the soil microbe Streptomyces |
|
|
Why is doxorubicin one of the most important anti-cancer drugs? |
It's active against both hematologic cancers and solid tumors |
|
|
What is the mechanism of doxorubicin? |
Inhibition of topoisomerase II, thereby preventing DNA replication |
|
|
What are two side effects of doxorubicin? |
Cardiotoxicity
Red urine |
|
|
Why does doxorubicin cause cardiotoxicity? |
It forms free radicals → oxidative stress |
|
|
How is doxorubicin metabolized, and why is it important? |
Metabolized in the liver by CYPs, so drug interactions with P450 modifiers are likely |
|
|
What type of drug is cyclophosphamide? |
An alkylating agent |
|
|
How were nitrogen mustard alkylating agents, like cyclophosphamide, originally used? |
Chemical warfare during WWI |
|
|
What is the mechanism of action of cyclophosphamide? |
Transfers alkyl groups to DNA, damaging it and cross-linking it |
|
|
Cyclophosphamide is especially toxic to ____ cells |
Dividing |
|
|
How does DNA alkylation cause cell death? |
Alkylation arrests the replication fork, triggering apoptotic signaling |
|
|
What is a major side effect of cyclophosphamide? |
Toxic to bone marrow |
|
|
How is cyclophosphamide used outside of cancer treatment? |
An immunosuppressant for organ transplant patients |
|
|
What is unique about cyclophosphamide metabolism? |
It is a prodrug activated by CYPs in the liver |
|
|
What race is especially prone to aggressive cancers? |
African Americans |
|
|
What is the standard therapy for late stage breast cancer? |
Adjuvant TAC therapy after surgery to remove the primary tumor |
|
|
What 3 drugs are utilized in TAC therapy? |
Docetaxel, doxorubicin, cyclophosphamide |
|
|
What type of drug is methotrexate? |
An anti-metabolite |
|
|
What compound is structurally similar to methotrexate? |
Folic acid |
|
|
What is the mechanism of action of methotrexate? |
It inhibits dihydrofolate reductase (DHFR), blocking the synthesis of tetrahydrofolate |
|
|
How does inhibition of DHFR lead to cell death? |
Tetrahydrofolate is a critical cofactor in the synthesis of thymidylate, nucleotides, and amino acids |
|
|
How is methotrexate used outside of cancer therapy? |
To treat arthritis and psoriasis |
|
|
Within the cell, methotrexate forms ____ derivatives that are retained within cancer cells |
Polyglutamate |
|
|
What complicates methotrexate dosing? |
It can accumulate in ascetic, pleural, or peritoneal fluid |
|
|
What drug interactions are important to remember for methotrexate? |
Drugs that bind to plasma proteins (salicylate, sulfonamides, phenytoin) |
|
|
What type of drug is 5-fluorouracil (5-FU)? |
An anti-metabolite |
|
|
What is the mechanism of 5-FU? |
Inhibits the biosynthesis of pyrimidines
Inhibits RNA function or processing
Inhibits thymidylate synthase |
|
|
What must happen to 5-FU in order for it to be active? |
It must be converted to a nucleotide, which is then incorporated into RNA or DNA |
|
|
How is 5-FU metabolized, and why is it important? |
5-FU is degraded by dihydropyrimidine dehydrogenase, and individuals with compromised function of this enzyme can experience profound drug toxicity |
|
|
What is the mechanism of tamoxifen? |
It is an inhibitor and partial agonist of the estrogen receptor |
|
|
What is tamoxifen used for? |
To treat late-stage hormone responsive breast cancer
Prevention of breast cancer in high risk patients |
|
|
How does tamoxifen affect the uterus? |
It has estrogenic activity |
|
|
How can tamoxifen have different activity in the breasts and the uterus? |
The estrogen receptor has multiple activities, which differ between the two organs |
|
|
What are the two mechanisms of ER transcriptional activation? |
Direct (binding to ERE)
Indirect (binding to other TF's) |
|
|
What are some side effects of tamoxifen? |
Hot flashes
Hair loss
Atrophy of the vaginal lining
2-3 fold increase in the risk of endometrial cancer |
|
|
How long is the half-life of tamoxifen? Why is this important? |
7-14 days
Fewer pills = better adherence to treatment regimen |
|
|
What type of drug is anastrozole? |
It is a non-steroidal inhibitor of aromatase (prevents estrogen synthesis) |
|
|
What is anastrozole used to treat? |
Estrogen receptor-positive breast cancer |
|
|
What is the mechanism of action of anastrozole? |
Binds to the heme group of CYP19/aromatase, preventing synthesis of estrogen |
|
|
Why is tamoxifen usually given before anastrozole to treat ER-positive breast cancer? |
Tamoxifen is fast-acting; anastrozole gradually depletes estrogen |
|
|
Is anastrozole associated with an increased risk of endometrial cancer? |
No |
|
|
Why are anti-emetic drugs an important part of chemotherapy? |
The intense nausea and vomiting caused by chemotherapy may cause patients to abandon their treatments prematurely |
|
|
Where are the chemoreceptor trigger zones (CTZ) and vomiting/emesis centers located? |
The medulla |
|
|
What types of receptors are abundant in the vomiting center? |
Histamine, 5-HT₃, dopamine, and cholinergic receptors |
|
|
What type of drug is ondansetron? |
An anti-emetic drug |
|
|
What is the mechanism of action of odansetron? |
It is an antagonist for the serotonin 5-HT₃ receptor (which is concentrated in the CTZ and other zones regulating nausea) |
|
|
What is important to remember about the pharmokinetics of odansetron? |
Its effects persist after it disappears from circulation, suggesting prolonged interaction with the 5-HT₃ receptor |
|
|
What percentage of breast cancer patients have elevated levels of HER-2/neu? EGFR? |
~20% |
|
|
How are HER-2/neu and EGFR related? |
They dimerize, and the resulting complex drives cell proliferation/angiogenesis |
|
|
What type of drug is trastuzumab/herceptin? |
A monoclonal antibody |
|
|
What is the mechanism of action of trastuzumab/herceptin? |
Binds and inhibits HER-2/neu |
|
|
What type of drug is cetuximab? |
A monoclonal antibody |
|
|
What is the mechanism of cetuximab? |
Binds and inhibits EGFR |
|
|
What type of drug is erlotinib? |
A small molecule inhibitor |
|
|
What is the mechanism of erlotinib? |
Blocks the intracellular functions of EGFR and HER-2/neu |
|
|
What type of drug is cetuximab? |
A recombinant monoclonal antibody |
|
|
How is cetuximab used? |
Administered to late stage lung cancer patients to extend lifespan by 2-4 months |
|
|
What is the mechanism of cetuximab? |
EGFR inhibitor |
|
|
Which group of people has a high rate of EGFR mutations? |
Asian women |
|
|
Besides smoking, what is a common cause of lung cancer? |
Mutations in the cytoplasmic domain on the EGFR receptor |
|
|
What type of receptor is EGFR? |
A receptor tyrosine kinase |
|
|
What are common side effects of erlotinib? Why? |
Rash and diarrhea
EGFR drives a major pathway in epithelial cell growth |
|
|
What is the most common GI malignancy? |
Colorectal cancer |
|
|
What is the primary drug for GI cancer? |
5-FU |
|
|
How is GI cancer treated after tumors develop resistance to 5-FU? |
Inhibition of angiogenesis |
|
|
What type of drug is bevacizumab? |
A monoclonal antibody |
|
|
What is the mechanism of action of bevacizumab? |
Binds VEGF and blocks its binding to VEGFR, preventing angiogenesis |
|
|
Why can't bevacizumab be administered within 28 days after surgery? And why does it cause GI bleeding? |
It blocks growth of blood vessels, so they may form weak structures |
|
|
Is childhood leukemia curable? |
Yes |
|
|
Which drug is used to prevent relapse of childhood leukemia? |
Methotrexate |
|
|
What is the mechanism of asparaginase, and what is it used to treat? |
It deprives leukemic cells of asparagine, which they do not synthesize or absorb |
|
|
What causes adult CML? |
Chromosome tranlocation resulting in Bcr-Abl oncogene |
|
|
What is the mechanism of imatinib? |
Inhibits Bcr-Abl fusion product |
|
|
What is Bcr-Abl? |
A highly active tyrosine kinase that drives cells to grow and not undergo apoptosis |
|
|
How effective is imatinib? |
Causes a complete response in about 1/2 of patients |
|
|
Does imatinib cure CML? |
No, resistance generally emerges following mutations in Bcr-Abl |
|
|
Are prostate cancers usually androgen-dependent or androgen-independent? |
Androgen-dependent |
|
|
What is the initial treatment for prostate cancer? |
Androgen deprivation therapy (ADT) using GnRH (gonadotropin-releasing hormone) agonists or AR (androgen receptor) inhibitors |
|
|
What is the effect of androgen deprivation therapy in prostate cancer patients? |
Treats primary symptoms (e.g. bone pain)
Lowers PSA levels |
|
|
How long after androgen deprivation therapy before prostate tumors become hormone-refractory? |
Within 2 years |
|
|
What type of drug is leuprolide? |
A GnRH agonist |
|
|
What is the mechanism of action of leuprolide? |
Binds to GnRH receptor and causes a surge in leutinizing hormone, leading to FSH release; transiently increases release of testosterone, but cells become desensitized and stop producing LH and FSH, decreasing testosterone production |
|
|
What is a side effect of leuprolide? |
A short-term increase in the disease (prostate cancer) due to GnRH surge |
|
|
How can the short-term increase in prostate cancer caused by leuprolide be suppressed? |
AR inhibitors |
|
|
What type of drug is flutamide? |
A non-steroidal AR inhibitor |
|
|
What is the mechanism of action of flutamide? |
Binds to AR, preventing its translocation to the nucleus |
|
|
What are the side effects of flutamide? |
Diarrhea, nausea, and reversible liver damage |
|
|
Why is malignant melanoma difficult to treat? |
The tumors are resistant to most drugs |
|
|
Which protein is mutated in 40-60% of all melanomas? |
B-Raf kinase |
|
|
What is the mechanism of action of vemurafenib? |
Inhibits mutant B-Raf-V600E in melanoma patients |
|
|
What is a drug that can be administered to patients at risk for melanoma? |
Topical fluorouracil |
|
|
What is a side effect of topical fluorouracil? |
Dramatic scarring |
|
|
Why does chemotherapy work poorly against brain cancer? |
Most drugs do not cross the BBB |
|
|
What is carmustine used to treat, and how is it administered? |
Brain cancers
Implanting drug-filled wafers |
|
|
What is the mechanism of action of carmustine? |
Alkylation of DNA on O⁶-guanine |
|
|
What are the side effects of carmustine? |
Nausea
Bone marrow toxicity
Moderate renal toxicity |
