Pharm E2- Onc

What are hyperplasia tumor cells?

inc in size or number of cells; function remains unchanged; reversible

What are metaplasia tumor cells?

adaptive substitution of one differentiated cell type for another differentiated cell type; protective response; some loss of function

ex: calluses; chronic irritation

What are dysplasia tumor cells?

loss of uniformity and architectural orientation; reversible

What is neoplasia?

uncoordinated growth, dec response to suppressor genes (P53, cyclin dependent kinases); immortalization (telomerase); irreversible

describe benign tumor cells

localized, enclosed in fibrous capsule

can be surgically removed and patients survive

describe malignant tumor cells

spreads to and destroys adjacent tissues, no capsule

metastasizes and patients can die

what is grade 1 tumor?

closely resembles tissue of origin and retains specialized function

what is a grade 2 tumor?

moderately differentiated and less like tissue of origin; increased mitosis

what is a grade 3 tumor?

poorly differentiated and doesn’t resemble tissue of origin; increased variation and increased mitosis

what is a grade 4 tumor?

very poorly differentiated and no resemblance of tissue of origin; highly variable, enhanced mitosis, and metastatic

What is gompertzian cell growth?

each tumor has constant time it takes to double it’s size

growth fraction (% of cells undergoing replication) dec as tumor size inc

a higher fraction = more aggressive

growth is initially rapid then flattens out as it outgrows the nutrient supply (fraction dec closer to plateau)

What cells do chemo treatments usually work better?

rapidly dividing cells (higher growth fraction)

What should the first step of treatment be?

removal of tumor (if possible), can be through surgery (well-localized and differentiated tumors), radiation (localized tumors not easily removed), chemotherapy (targets all rapidly diving cells, system, inc chances against metastatic cells)

Why is myelosuppresion a significant toxicity?

increases risk for infections

Why are some drugs dosed on an intermittent schedule?

high dosages, toxic to all cells, so it allows for recovery of RBCs

What is mitosis?

cell division, 30-60 minutes

what is G0?

resting phase, no division

what is G1?

post mitotic phase, enzyme synthesis prior to DNA synthesis, 18-30 hours

What is the S phase?

DNA synthesis, 10-20 hours

What is G2?

pre-mitotic phase, protein and RNA synthesis, 2-10 hours

What phase are most non-malignant cells in?

G0

what is growth fraction?

proportion of cells that are actively dividing in early stages of growth

What is S fraction?

percentage of cells in S phase → implies aggressiveness of tumor

What is doubling time?

time necessary for tumor to double in volume

What does a short doubling time indicate?

aggressive tumor

What are benefits of combination therapy?

minimize resistance and toxic effects

What is adjuvant therapy?

treat/minimize toxic effects (treating the pt, not the cancer)

ex: antiemetic drugs; stimulating bone marrow growth

What is cell cycle specific chemotherapy?

only targets cell as they are in a particular phase; given as continuous infusions or as multiple doses in close timeframe to target all cells hitting that phase

What is non-cell cycle specific chemotherapy?

not schedule dependent (dose dependent); can be given at any time

What is targeted therapy?

small molecules that target specific extracellular receptors

How do biologics tx cancer?

boosts host immune system to fight cancerous cells

What are cells with the highest growth rates that are affected by chemotherapy?

neoplastic cells (desired), bone marrow (immune suppression), GI tract (stomatitis), hair (alopecia), reproductive cells (sperm/menstrual irregularities)

What are antimetabolites?

look similar to the nucleotides that makeup DNA/RNA, disrupt replication/cell division by preventing production of nucleic acids

not selective for cancerous cells

What are the 3 categories of antimetabolites?

pyrimidine analogs, purine analogs, folate antagonists

What are examples of pyrimidine analogs?

cytarabine (AraC, cytosar)

Gemcitabine (Gemzar)

Fluorouracil (5-FU)

What is the mechanism of Cytarabine (AraC, Cytostar)?

cytidine analog that becomes phosphorylated and inhibits DNA polymerase → disrupts strand elongation → becomes incorporated into DNA and acts as chain terminator

What is cytarabine (AraC, Cytosar)?

pyrimidine (cytidine) analog that is used to treat many types of leukemia

given intravenously or intrathecally

What are toxicities associated w/ Cytarabine (AraC, Cytosar)?

cerebellar syndrome (large doses) → dysarthria, nystagmus, and ataxia; seen w/ renal dysfunction

conjunctivitis/keratitis ( steroid eye drops or saline eye drops)

What toxicities are seen in most cancer treatments?

nausea, vomiting, mucositis, myelosuppression

What is the mechanism of Gemcitabine (Gemzar)?

fluorine substituted deoxycytidine analog that:

- inhibits DNA polymerase upon incorporation into DNA

- inhibits ribonucleotide reductase → prevents deoxyribonucleotide production

What are toxicities w/ Gemcitabine (Gemzar)?

flu like sx - can be pretreated w/ acetaminophen

What is the mechanism of fluorouracil (5-FU)?

incorporated into RNA to inhibit function

false pyrimidine that inhibits thymidylate synthase (produces new nucleotides) and inhibits thymidine formation

What is Fluorouracil (5-FU)?

pyrimidine analog; converted from capecitabine (Xeloda)

used to treat many types of leukemia

What are toxicities w/ Fluorouracil (5-FU)?

cerebellar syndrome (large doses) → dysarthria, nystagmus, ataxia; seen w/ renal dysfunction

Hand-foot syndrome - paresthesias “stocking glove”

conjunctivitis / keratitis

What is examples of purine analogs?

6-Mercaptopurine (6-MP, Purinethol)

Thioguanine (Tabloid)

What is the mechanism of Thioguanine (Tabloid)?

prevent purine synthesis (adenine, guanine); incorporated into DNA and inhibits DNA polymerase

used to treat ALL

What are toxicities w/ Thioguanine (Tabloid)?

hepatotoxicity and myelosuppression due to toxic metabolites

pharmocogenetic changes in enzyme expression can lead to worse toxicitiy

What is Methotrexate (MTX, Rheumatrex)?

folate antagonist used in ALL, some lymphomas, and rheumatologist conditions

can be given orally, IV, or intrathecally

What is the mechanism of Methotrexate (MTX, Rheumatrex)?

inhibits dihydrofolate reductase (DHFR) (inhibits recycling of folic acid)

reduced tetrahydrofolate stores

dec thymidylate and purine synthesis

dec RNA/DNA production

What are toxicities w/ Methotrexate (MTX, Rheumatrex)?

Hepatotoxicity (don’t drink alcohol)

renal toxicity due to precipitation in the renal tubules

highly protein bound to albumin → drugs displacing it may inc toxicity

What are antidotes for MTX?

folinic acid (Leucovorin) - “leucovorin rescue”

sodium bicarbonate

Glucarpidase (Voraxaze)

How is folinic acid (Leucovorin) an antidote for MTX?

reduces folate and bypasses DHFR block (dosing and duration determined by MTX levels)

How is sodium bicarbonate an antidote for MTX?

alkalinizes urine to prevent precipitation and enhance elimination

How is Glucarpidase (Voraxaze) an antidote for MTX?

directly metabolizes MTX; good for patients w/ renal failure or very high levels but its expensive

What are microtubules?

integral part of cytoskeleton- provides cell structure, helps separate chromosomes, and forms mitotic spindle during cell replication

What drugs affect microtubule function?

taxanes and vinca alkaloids

What are examples of Taxanes (plant alkaloids)?

Paclitaxel (Taxol) and Docetaxel (Taxotere)

What is the mechanism of Taxanes?

promotes microtubule formation and prevents breakdown

forms stable nonfunctional microtubules that prevent functions like mitosis

What do Paclitaxel and Docetaxel require to limit SE?

pretreatment w/ corticosteroids

What toxicities are w/ Docetaxel?

fluid retention

What toxicities are w/ Paclitaxel?

neurotoxicity (peripheral neuropathies), and hypersensitivity

What are examples of Vinca Alkaloids?

Vincristine (VCR, Vincasar)

Vinblastine (VBL)

Vinorelbine (Navelbine)

What is the mechanism of Vinca Alkaloids?

bind to tubular and disrupt formation of microtubules → cells cannot complete mitosis

What toxicities are seen w/ Vinca Alkaloids?

fatal if given intrathecally

VBL and vinorelbine- dose limiting myelosuppression

VCR- dose limiting neurotoxicity (hand foot syndrome, paralytic ileum/constipation)

vesicants

Which Topoisomerase causes single strand breaks?

I

Which topoisomerase causes double strand breaks?

II

What does topoisomerase I and II do?

break and reseal DNA strands allowing for winding/unwinding of DNA structures

What are the classes of Topoisomerase inhibitors?

epipodophyllotoxins, anthracyclines, camptothecins

What are examples of Epipodophyllotoxins?

Etoposide (Toposar)

Teniposide (Vumon)

What is the mechanism of Epipodophyllotoxins?

bind to tubular and inhibit microtubule formation, cause DNA strand breakage by inhibiting topoisomerase II

What toxities are seen w/ Epipodophyllotoxins?

dose limiting myelosuppression, N, V, alopecia

What are examples of anthracyclines?

Doxorubicin (Adriamycin)

Daunorubicin

Mitoxantrone

What is the mechanism of anthracyclines?

inhibit topoisomerase II, intercalate into DNA, free radical production

What toxicities are seen w/ anthracyclines?

cardiomyopathy and CHF (due to limited ability of myocardium to detoxify free radicals)

alopecia

red discoloration or urine, sweat, etc

strong vesicants

what is the antidote for anthracyline induced cardiomyopathy? (possible test Q)

dexrazoxane (zinecard) - chelates iron to prevent free radical generation → cardioprotective

What are examples of camptothecins?

topotecan (hycamtin) and irinotecan (camptosar)

What is the mechanism of camptothecins?

inhibit topoisomerase I

What are toxicities w/ captothecins?

diarrhea (irinotecan » topotecan)

alopecia

dec cholinesterase activity (irinotecan)

What are the oldest and most useful classes of chemotherapy?

alkylating agents

What is the mechanism of alkylating agents?

covalently bind to alkyl groups in proteins and DNA → trigger apoptosis

may cross link b/t strands or b/t bases in same strand

cell cycle non-specific

What are toxicities of alkylating agents?

cytotoxic, mutagenic, teratogenic, carcinogenic, myelosuppresive, pulmonary fibrosis, and very emetogenic

What are examples of nitrogen mustards?

cyclophosphamide (CPM)

Ifosfamide (Ifex)

What are nitrogen mustards used to tx?

many solid tumors and hematologic cancers (wide range bc non cell cycle specific)

What are toxicities seen w/ nitrogen mustards?

forms toxic metabolites - acrolein, hemorrhagic cystitis, CNS toxicity - encephalopathy (more w/ ifosfamide), renal toxicity

What is the antidote for nitrogen mustards?

Mesna- binds to and inactivates acrolein → prevents hemorrhagic cystitis

should be administered w/ vigorous hydration

What are examples of Nitrosoureas?

Carmustine (BCNU, Gliadel)

Lomustine (CCNU, Gleostine)

What are nitrosoureas used to tx?

brain cancers due to lipophilicity and prep for bone marrow transplant

What are toxicities seen w/ nitrosoureas?

most myelosuppressive (possibly fatal),

nadir can be delayed (4-6 weeks)and last a long time (up to 2 weeks)

What are examples of platinum analogs?

Cisplatin, Carboplatin, Oxaliplatin (Eloxatin)

What is the mechanism of platinum analogs?

bind to and distort DNA structure preventing bases from lining up appropriately

What are toxicities w/ platinum analogs?

nephrotoxicity (managed w. vigorous hydration)

ototoxicity

peripheral neuropathy

hypersensitivity / anaphylaxis risk

severe N/V

What is the mechanism of dacarbazine and temozolomide (temodar)?

metabolized to MTIC that methylates guanine → inhibits DNA, RNA, and protein synthesis

What is Busulfan (Myeleran)?

alkylator that acts similar to nitrogen mustards

toxicities: myelosuppression, GI, pulmonary fibrosis, seizures, hepatotoxicity

monitor PFTs

How does androgen/estrogen therapy work?

effective for hormone sensitive cancers → prostate, breast, endometrial

aims to antagonize receptors or prevent production of sex hormones

How does corticosteroid therapy work?

used for lymphotoxin effects like leukemia → suppresses WBCs

can also treat chemo induced N/V

prednisone, dexamethasone, etc

What is tamoxifen (nolvadex)?

estrogen partial agonist (SERM) that competes w/ estrogen for receptor binding

tx estrogen dependent breast tumors

What toxicities are seen w/ tamoxifen (nolvadex)?

hot flashes

N/V/ myelosuppression

DVT: estrogen in liver → upregulates clotting factors

pulmonary embolism

linked to endometrial cancer

Where does Tamoxifen have positive estrogenic effects?

bone and cholesterol

What is Raloxifene (Evista)?

selective estrogen receptor modulator (SERM) used mainly in osteoporosis

antagonist in breast and uterine tissue ; estrogen eggiests in bone and CV system

What is Fulvestrant (Faslodex)?

selective estrogen receptor down regulator (SERD)

monthly IM injection w/ pure anti-estrogen activity